3-((Hetero-)Aryl)-8-Amino-2-Oxo-1,3-Diaza-Spiro-[4.5]-Decane Derivatives

ABSTRACT

The invention relates to 3-((hetero-)aryl)-8-amino-2-oxo-1,3-diaza-spiro-[4.5]-decane derivatives, their preparation and their use in medicine, particularly in the treatment of pain.

This application is a continuation of U.S. patent application Ser. No. 17/010,089, filed Sep. 2, 2020, pending, which is a continuation of U.S. patent application Ser. No. 16/450,331, filed Jun. 24, 2019, now U.S. Pat. No. 10,807,988, which is a continuation of U.S. patent application Ser. No. 16/207,854, filed Dec. 3, 2018, abandoned, which is a continuation of U.S. patent application Ser. No. 15/923,948, filed Mar. 16, 2018, abandoned; which is a continuation of U.S. patent application Ser. No. 15/405,485, filed Jan. 13, 2017, abandoned; which claims foreign priority benefit under 35 U.S.C. § 119 of European Patent Application No. 16 151 012.8, filed Jan. 13, 2016, the disclosures of which are incorporated herein by reference.

The invention relates to 3-((hetero-)aryl)-8-amino-2-oxo-1,3-diaza-spiro-[4.5]-decane derivatives, their preparation and use in medicine, particularly in various neurological disorders, including but not limited to pain, neurodegenerative disorders, neuroinflammatory disorders, neuropsychiatric disorders, substance abuse/dependence.

Opioid receptors are a group of Gi/o protein-coupled receptors which are widely distributed in the human body. The opioid receptors are currently subdivided into four major classes, i.e. the three classical opioid receptors mu-opioid (MOP) receptor, kappa-opioid (KOP) receptor, and delta-opioid (DOP) receptor as well as the opioid receptor-like (ORL-1) receptor, which was more recently discovered based on its high homology with said classical opioid receptors. After identification of the endogenous ligand of the ORL-1 receptor, known as nociceptin/orphanin FQ, a highly basic 17 amino acid peptide isolated from tissue extracts in 1995, the ORL-1 receptor was renamed “nociceptin opioid peptide receptor” and abbreviated as “NOP-receptor”.

The classical opioid receptors (MOP, KOP and DOP) as well as the NOP receptor are widely distributed/expressed in the human body, including in the brain, the spinal cord, on peripheral sensory neurons and the intestinal tract, wherein the distribution pattern differs between the different receptor classes.

Nociceptin acts at the molecular and cellular level in very much the same way as opioids. However, its pharmacological effects sometimes differ from, and even oppose those of opioids. NOP-receptor activation translates into a complex pharmacology of pain modulation, which, depending on route of administration, pain model and species involved, leads to either pronociceptive or antinociceptive activity. Furthermore, the NOP receptor system is upregulated under conditions of chronic pain. Systemic administration of selective NOP receptor agonists was found to exert a potent and efficacious analgesia in non-human primate models of acute and inflammatory pain in the absence of side effects. The activation of NOP receptors has been demonstrated to be devoid of reinforcing effects but to inhibit opioid-mediated reward in rodents and non-human primates (Review: Schroeder et al, Br J Pharmacol 2014; 171 (16): 3777-3800, and references therein).

Besides the involvement of the NOP receptor in nociception, results from preclinical experiments suggest that NOP receptor agonists might be useful inter alia in the treatment of neuropsychiatric disorders (Witkin et al, Pharmacology & Therapeutics, 141 (2014) 283-299; Jenck et al., Proc. Natl. Acad. Sci. USA 94, 1997, 14854-14858). Remarkably, the DOP receptor is also implicated to modulate not only pain but also neuropsychiatric disorders (Mabrouk et al, 2014; Pradhan et al., 2011).

Strong opioids acting at the MOP receptor site are widely used to treat moderate to severe acute and chronic pain. However, the therapeutic window of strong opioids is limited by severe side effects such as nausea and vomiting, constipation, dizziness, somnolence, respiratory depression, physical dependence and abuse. Furthermore, it is known that MOP receptor agonists show only reduced effectiveness under conditions of chronic and neuropathic pain.

It is known that some of the above mentioned side-effects of strong opioids are mediated by activation of classic opioid-receptors within the central nervous system. Furthermore, peripheral opioid receptors, when activated, can inhibit transmission of nociceptive signals shown in both, clinical and animal studies (Gupta et al., 2001; Kalso et al., 2002; Stein et al., 2003; Zollner et al., 2008).

Thus, to avoid CNS-mediated adverse effects after systemic administration, one approach has been to provide peripherally restricted opioid receptor ligands that do not easily cross the blood-brain barrier and therefore distribute poorly to the central nervous system (see for instance WO 2015/192039). Such peripherally acting compounds might combine effective analgesia with limited side-effects.

Another approach has been to provide compounds which interact with both the NOP receptor and the MOP receptor. Such compounds have for instance been described in WO 2004/043967, WO 2012/013343 and WO 2009/118168.

A further approach has been to provide multi-opioid receptor analgesics that modulate more than one of the opioid receptor subtypes to provide additive or synergistic analgesia and/or reduced side effects like abuse liability or tolerance.

On the one hand, it would be desirable to provide analgesics that selectively act on the NOP receptor system but less pronounced on the classic opioid receptor system, especially MOP receptor system, whereas it would be desirable to distinguish between central nervous activity and peripheral nervous activity. On the other hand, it would be desirable to provide analgesics that act on the NOP receptor system and also to a balanced degree on the MOP receptor system, whereas it would be desirable to distinguish between central nervous activity and peripheral nervous activity.

There is a need for medicaments which are effective in the treatment of pain and which have advantages compared to the compounds of the prior art. Where possible, such medicaments should contain such a small dose of active ingredient that satisfactory pain therapy can be ensured without the occurrence of intolerable treatment-emergent adverse events.

It is an object of the invention to provide pharmacologically active compounds, preferably analgesics that have advantages compared to the prior art.

This object has been achieved by the subject-matter of the patent claims.

A first aspect of the invention relates to 3-((hetero-)aryl)-8-amino-2-oxo-1,3-diaza-spiro-[4.5]-decane derivatives according to general formula (I)

wherein R¹ and R² independently of one another mean

—H;

—C₁-C₆-alkyl, linear or branched, saturated or unsaturated, unsubstituted or substituted with one, two, three or four substituents independently of one another selected from the group consisting of —F, —Cl, —Br, —I, —OH, —OCH₃, —CN and —CO₂CH₃; a 3-12-membered cycloalkyl moiety, saturated or unsaturated, unsubstituted or substituted with one, two, three or four substituents independently of one another selected from the group consisting of —F, —Cl, —Br, —I, —OH, —OCH₃, —CN and —CO₂CH₃; wherein said 3-12-membered cycloalkyl moiety is optionally connected through —C₁-C₆-alkylene-, linear or branched, saturated or unsaturated, unsubstituted; or a 3-12-membered heterocycloalkyl moiety, saturated or unsaturated, unsubstituted or substituted with one, two, three or four substituents independently of one another selected from the group consisting of —F, —Cl, —Br, —I, —OH, —OCH₃, —CN and —CO₂CH₃; wherein said 3-12-membered heterocycloalkyl moiety is optionally connected through —C₁-C₆-alkylene-, linear or branched, saturated or unsaturated, unsubstituted; or R¹ and R² together with the nitrogen atom to which they are attached form a ring and mean —(CH₂)₃₋₆—; —(CH₂)₂—O—(CH₂)₂—; or —(CH₂)₂—NR^(A)—(CH₂)₂—, wherein R^(A) means —H or —C₁-C₆-alkyl, linear or branched, saturated or unsaturated, unsubstituted or substituted with one, two, three or four substituents independently of one another selected from the group consisting of —F, —Cl, —Br and —I; preferably with the proviso that R¹ and R² do not simultaneously mean —H; R³ means —C₁-C₆-alkyl, linear or branched, saturated or unsaturated, unsubstituted, mono- or polysubstituted; a 3-12-membered cycloalkyl moiety, saturated or unsaturated, unsubstituted, mono- or polysubstituted; wherein said 3-12-membered cycloalkyl moiety is optionally connected through —C₁-C₆-alkylene-, linear or branched, saturated or unsaturated, unsubstituted, mono- or polysubstituted; a 3-12-membered heterocycloalkyl moiety, saturated or unsaturated, unsubstituted, mono- or polysubstituted; wherein said 3-12-membered heterocycloalkyl moiety is optionally connected through —C₁-C₆-alkylene-, linear or branched, saturated or unsaturated, unsubstituted, mono- or polysubstituted; a 6-14-membered aryl moiety, unsubstituted, mono- or polysubstituted; wherein said 6-14-membered aryl moiety is optionally connected through —C₁-C₆-alkylene-, linear or branched, saturated or unsaturated, unsubstituted, mono- or polysubstituted; or a 5-14-membered heteroaryl moiety, unsubstituted, mono- or polysubstituted; wherein said 5-14-membered heteroaryl moiety is optionally connected through —C₁-C₆-alkylene-, linear or branched, saturated or unsaturated, unsubstituted, mono- or polysubstituted; R⁴ means

—H;

—C₁-C₆-alkyl, linear or branched, saturated or unsaturated, unsubstituted, mono- or polysubstituted; wherein said —C₁-C₆-alkyl is optionally connected through —C(═O)—, —C(═O)O—, or —S(═O)₂—; a 3-12-membered cycloalkyl moiety, saturated or unsaturated, unsubstituted, mono- or polysubstituted; wherein said 3-12-membered cycloalkyl moiety is optionally connected through —C₁-C₆-alkylene-, linear or branched, saturated or unsaturated, unsubstituted, mono- or polysubstituted; or wherein said 3-12-membered cycloalkyl moiety is optionally connected through —C(═O)—, —C(═O)O—, —C(═O)O—CH₂—, or —S(═O)₂—; a 3-12-membered heterocycloalkyl moiety, saturated or unsaturated, unsubstituted, mono- or polysubstituted; wherein said 3-12-membered heterocycloalkyl moiety is optionally connected through —C₁-C₆-alkylene-, linear or branched, saturated or unsaturated, unsubstituted, mono- or polysubstituted; or wherein said 3-12-membered heterocycloalkyl moiety is optionally connected through —C(═O)—, —C(═O)O—, —C(═O)O—CH₂—, or —S(═O)₂—; a 6-14-membered aryl moiety, unsubstituted, mono- or polysubstituted; wherein said 6-14-membered aryl moiety is optionally connected through —C₁-C₆-alkylene-, linear or branched, saturated or unsaturated, unsubstituted, mono- or polysubstituted; or wherein said 6-14-membered aryl moiety is optionally connected through —C(═O)—, —C(═O)O—, —C(═O)O—CH₂—, or —S(═O)₂—; or a 5-14-membered heteroaryl moiety, unsubstituted, mono- or polysubstituted; wherein said 5-14-membered heteroaryl moiety is optionally connected through —C₁-C₆-alkylene-, linear or branched, saturated or unsaturated, unsubstituted, mono- or polysubstituted; or wherein said 5-14-membered heteroaryl moiety is optionally connected through —C(═O)—, —C(═O)O—, —C(═O)O—CH₂—, or —S(═O)₂—; R⁵ means a 6-14-membered aryl moiety, unsubstituted, mono- or polysubstituted; or a 5-14-membered heteroaryl moiety, unsubstituted, mono- or polysubstituted; R¹¹, R¹², R¹³, R¹⁴, R¹⁵, R¹⁶, R¹⁷, R¹⁸, R¹⁹, and R²⁰ independently of one another mean —H, —F, —Cl, —Br, —I, —OH, or —C₁-C₆-alkyl, linear or branched, saturated or unsaturated, unsubstituted, mono- or polysubstituted; wherein “mono- or polysubstituted” means that one or more hydrogen atoms are replaced by a substituent independently of one another selected from the group consisting of —F, —Cl, —Br, —I, —CN, —R²¹, —C(═O)R²¹, —C(═O)OR²¹, —C(═O)NR²¹R²², —C(═O)NH—(CH₂CH₂—O)₁₋₃₀—CH₃, —O—(CH₂CH₂—O)₁₋₃₀—H, —O—(CH₂CH₂—O)₁₋₃₀—CH₃, ═O, —OR²¹, —OC(═O)R²¹, —OC(═O)OR²¹, —OC(═O)NR²¹R²², —NO₂, —NR²¹R²², —NR²¹—(CH₂)₁₋₆—C(═O)R²², —NR²¹—(CH₂)₁₋₆—C(═O)OR²², —NR²³—(CH₂)₁₋₆—C(═O)NR²¹R²², —NR²¹C(═O)R²², —NR²¹C(═O)—OR²², —NR²³C(═O)NR²¹R²², —NR²¹S(═O)₂R²², —SR²¹, —S(═O)R²¹, —S(═O)₂R²¹, —S(═O)₂OR²¹, and —S(═O)₂NR²¹R²²; wherein R²¹, R²² and R²³ independently of one another mean

—H;

—C₁-C₆-alkyl, linear or branched, saturated or unsaturated, unsubstituted or substituted with one, two, three or four substituents independently of one another selected from the group consisting of —F, —Cl, —Br, —I, —CN, —OH, —NH₂, —C₂H, —C(═O)O—C₁-C₆-alkyl, —C(═O)NH₂, —C(═O)NHC₁-C₆-alkyl, —C(═O)N(C₁-C₆-alkyl)₂, —O—C₁-C₆-alkyl and —S(═O)₂—C₁-C₆-alkyl; a 3-12-membered cycloalkyl moiety, saturated or unsaturated, unsubstituted, mono- or polysubstituted; wherein said 3-12-membered cycloalkyl moiety is optionally connected through —C₁-C₆-alkylene-, linear or branched, saturated or unsaturated, unsubstituted or substituted with one, two, three or four substituents independently of one another selected from the group consisting of —F, —Cl, —Br, —I, —CN, —OH, —NH₂, —C₁-C₆-alkyl and —O—C₁-C₆-alkyl; a 3-12-membered heterocycloalkyl moiety, saturated or unsaturated, unsubstituted, mono- or polysubstituted; wherein said 3-12-membered heterocycloalkyl moiety is optionally connected through —C₁-C₆-alkylene-, linear or branched, saturated or unsaturated, unsubstituted or substituted with one, two, three or four substituents independently of one another selected from the group consisting of —F, —Cl, —Br, —I, —CN, —OH, —NH₂, —C₁-C₆-alkyl and —O—C₁-C₆-alkyl; a 6-14-membered aryl moiety, unsubstituted, mono- or polysubstituted; wherein said 6-14-membered aryl moiety is optionally connected through —C₁-C₆-alkylene-, linear or branched, saturated or unsaturated, unsubstituted or substituted with one, two, three or four substituents independently of one another selected from the group consisting of —F, —Cl, —Br, —I, —CN, —OH, —NH₂, —C₁-C₆-alkyl and —O—C₁-C₆-alkyl; a 5-14-membered heteroaryl moiety, unsubstituted, mono- or polysubstituted; wherein said 5-14-membered heteroaryl moiety is optionally connected through —C₁-C₆-alkylene-, linear or branched, saturated or unsaturated, unsubstituted or substituted with one, two, three or four substituents independently of one another selected from the group consisting of —F, —Cl, —Br, —I, —CN, —OH, —NH₂, —C₁-C₆-alkyl and —O—C₁-C₆-alkyl; or R²¹ and R²² within —C(═O)NR²¹R²², —OC(═O)NR²¹R²², —NR²¹R²², —NR²³—(CH₂)₁₋₆—C(═O)NR²¹R²², —NR²³C(═O)NR²¹R²², or —S(═O)₂NR²¹R²² together with the nitrogen atom to which they are attached form a ring and mean —(CH₂)₃₋₆—; —(CH₂)₂—O—(CH₂)₂—; —(CH₂)₂—S(═O)₂—(CH₂)₂— or —(CH₂)₂—NR^(B)—(CH₂)₂—, wherein R^(B) means —H, —C₁-C₆-alkyl, —C(═O)—C₁-C₆-alkyl, or —S(═O)₂—C₁-C₆-alkyl, wherein said —C₁-C₆-alkyl is linear or branched, saturated or unsaturated, unsubstituted or substituted with one, two, three or four substituents independently of one another selected from the group consisting of —F, —Cl, —Br —I, —OH, —CO₂H, —C(═O)O—C₁-C₆-alkyl and —C(═O)NH₂; and wherein said ring is unsubstituted or substituted with one, two, three or four substituents independently of one another selected from the group consisting of —F, —Cl, —Br, —I, —CN, —OH, —NH₂, —C₁-C₆-alkyl and —O—C₁-C₆-alkyl; or a physiologically acceptable salt thereof.

“(Hetero-)aryl” means “heteroaryl or aryl”. Preferably, aryl includes but is not limited to phenyl and naphthyl. Preferably, heteroaryl includes but is not limited to -1,2-benzodioxole, -pyrazinyl, -pyridazinyl, -pyridinyl, -pyrimidinyl, -thienyl, -imidazolyl, -benzimidazolyl, -thiazolyl, -1,3,4-thiadiazolyl, -benzothiazolyl, -oxazolyl, -benzoxazolyl, -pyrazolyl, -quinolinyl, -isoquinolinyl, -quinazolinyl, -indolyl, -indolinyl, -benzo[c][1,2,5]oxadiazolyl, -imidazo[1,2-a]pyrazinyl, or -1H-pyrrolo[2,3-b]pyridinyl. Preferably, cycloalkyl includes but is not limited to -cyclopropyl, -cyclobutyl, -cyclopentyl and -cyclohexyl. Preferably, heterocycloalkyl includes but is not limited to -aziridinyl, -azetidinyl, -pyrrolidinyl, -piperidinyl, -piperazinyl, -morpholinyl, -sulfamorpholinyl, -oxiridinyl, -oxetanyl, -tetrahydropyranyl, and -pyranyl.

When a moiety is connected through an asymmetric group such as —C(═O)O— or —C(═O)O—CH₂—, said asymmetric group may be arranged in either direction. For example, when R⁴ is connected to the core structure through —C(═O)O—, the arrangement may be either R⁴—C(═O)O-core or core-C(═O)O—R⁴.

In preferred embodiments of the compound according to the invention, R¹¹, R¹², R¹³, R¹⁴, R¹⁵, R¹⁶, R¹⁷, R¹⁸, R¹⁹, and R²⁰ independently of one another mean —H, —F, —OH, or —C₁-C₆-alkyl; preferably —H.

In a preferred embodiment of the compound according to the invention, R¹ means —H; and R² means —C₁-C₆-alkyl, linear or branched, saturated or unsaturated, unsubstituted, mono- or polysubstituted. Preferably, R¹ means —H and R² means —CH₃.

In another preferred embodiment of the compound according to the invention, R¹ means —CH₃; and R² means —C₁-C₆-alkyl, linear or branched, saturated or unsaturated, unsubstituted, mono- or polysubstituted. Preferably, R¹ means —CH₃ and R² means —CH₃.

In still another preferred embodiment of the compound according to the invention, R¹ and R² together with the nitrogen atom to which they are attached form a ring and mean —(CH₂)₃₋₆—. Preferably, R¹ and R² together with the nitrogen atom to which they are attached form a ring and mean —(CH₂)₃—.

In yet another preferred embodiment,

-   -   R¹ means —H or —CH₃; and     -   R² means a 3-12-membered cycloalkyl moiety, saturated or         unsaturated, unsubstituted; wherein said 3-12-membered         cycloalkyl moiety is connected through —CH₂—, unsubstituted;         preferably —CH₂-cycloalkyl, —CH₂-cyclobutyl or —CH₂-cyclopentyl;         or R² means a 3-12-membered heterocycloalkyl moiety, saturated         or unsaturated, unsubstituted; wherein said 3-12-membered         heterocycloalkyl moiety is connected through —CH₂—,         unsubstituted; preferably —CH₂-oxetanyl or         —CH₂-tetrahydrofuranyl.

In a preferred embodiment of the compound according to the invention, R³ means —C₁-C₆-alkyl, linear or branched, saturated or unsaturated, unsubstituted, mono- or polysubstituted. Preferably, R³ means —C₁-C₆-alkyl, linear or branched, saturated or unsaturated, unsubstituted or monosubstituted with —OCH₃.

In another preferred embodiment of the compound according to the invention, R³ means a 6-14-membered aryl moiety, unsubstituted, mono- or polysubstituted, optionally connected through —C₁-C₆-alkylene-, linear or branched, saturated or unsaturated, unsubstituted. In a preferred embodiment, R³ means -phenyl unsubstituted, mono- or polysubstituted. More preferably, R³ means -phenyl unsubstituted, mono- or disubstituted with —F, —Cl, —CH₃, —CF₃, —OH, —OCH₃, —OCF₃ or —OCH₂OCH₃, preferably —F. In another preferred embodiment, R³ means -benzyl unsubstituted, mono- or polysubstituted. More preferably, R³ means -benzyl unsubstituted, mono- or disubstituted with —F, —Cl, —CH₃, —CF₃, —OH, —OCH₃, —OCF₃ or —OCH₂OCH₃, preferably —F.

In still another preferred embodiment of the compound according to the invention, R³ means a 5-14-membered heteroaryl moiety, unsubstituted, mono- or polysubstituted. Preferably, R³ means -thienyl or -pyridinyl, in each case unsubstituted, mono- or polysubstituted. More preferably, R³ means -thienyl, -pyridinyl, -imidazolyl or benzimidazolyl, in each case unsubstituted or monosubstituted with —F, —Cl or —CH₃.

In a preferred embodiment of the compound according to the invention, R⁴ means —H.

In another preferred embodiment of the compound according to the invention, R⁴ means —C₁-C₆-alkyl, linear or branched, saturated or unsaturated, unsubstituted, mono- or polysubstituted. Preferably, R⁴ means —C₁-C₆-alkyl, linear or branched, saturated or unsaturated, unsubstituted or monosubstituted with a substituent selected from the group consisting of —F, —Cl, —Br, —I, —CN, —CF₃, —OH, —O—C₁-C₄-alkyl, —OCF₃, —O—(CH₂CH₂—O)₁₋₃₀—H, —O—(CH₂CH₂—O)₁₋₃₀—CH₃, —OC(═O)C₁-C₄-alkyl, —C(═O)C₁-C₄-alkyl, —C(═O)OH, —C(═O)OC₁-C₄-alkyl, —C(═O)NH₂, —C(═O)NHC₁-C₄-alkyl, —C(═O)NHC₁-C₄-alkylene-CN, —C(═O)NHC₁-C₄-alkylene-O—C₁-C₄-alkyl, —C(═O)N(C₁-C₄-alkyl)₂; —S(═O)C₁-C₄-alkyl, and —S(═O)₂C₁-C₄-alkyl; or with —C(═O)NR²¹R²² wherein R²¹ and R²² together with the nitrogen atom to which they are attached form a ring and mean —(CH₂)₃₋₆—, —(CH₂)₂—O—(CH₂)₂—, or —(CH₂)₂—NR^(B)—(CH₂)₂—, wherein R^(B) means —H or —C₁-C₆-alkyl; or with —C(═O)NH-3-12-membered cycloalkyl, saturated or unsaturated, unsubstituted or monosubstituted with —F, —Cl, —Br, —I, —CN, or —OH; or with —C(═O)NH-3-12-membered heterocycloalkyl, saturated or unsaturated, unsubstituted or monosubstituted with —F, —Cl, —Br, —I, —CN, or —OH. More preferably, R⁴ means —C₁-C₆-alkyl, linear or branched, saturated or unsaturated, unsubstituted or monosubstituted with —O—C₁-C₄-alkyl or —C(═O)N(C₁-C₄-alkyl)₂.

In still another preferred embodiment of the compound according to the invention, R⁴ means a 3-12-membered cycloalkyl moiety, saturated or unsaturated, unsubstituted, mono- or polysubstituted; wherein the 3-12-membered cycloalkyl moiety is connected through —C₁-C₆-alkylene-, linear or branched, saturated or unsaturated, unsubstituted, mono- or polysubstituted. Preferably, R⁴ means a 3-12-membered cycloalkyl moiety, saturated or unsaturated, unsubstituted, mono- or polysubstituted; wherein said 3-12-membered cycloalkyl moiety is connected through —CH₂— or —CH₂CH₂—. More preferably, R⁴ means a 3-12-membered cycloalkyl moiety, saturated or unsaturated, unsubstituted or substituted with one, two, three or four substituents independently of one another selected from the group consisting of —F, —Cl, —Br, —I, —CN, —OH, —C₁-C₄-alkyl, —O—C₁-C₄-alkyl, —C(═O)OH, —C(═O)OC₁-C₄-alkyl, —C(═O)NH₂, —C(═O)NHC₁-C₄-alkyl, —C(═O)N(C₁-C₄-alkyl)₂, —S(═O)C₁-C₄-alkyl and —S(═O)₂C₁-C₄-alkyl; wherein said 3-12-membered cycloalkyl moiety is connected through —CH₂— or —CH₂CH₂—.

In a preferred embodiment of the compound according to the invention, R⁴ means a 3-12-membered heterocycloalkyl moiety, saturated or unsaturated, unsubstituted, mono- or polysubstituted; wherein said 3-12-membered heterocycloalkyl moiety is connected through —C₁-C₆-alkylene-, linear or branched, saturated or unsaturated, unsubstituted, mono- or polysubstituted. Preferably, R⁴ means a 3-12-membered heterocycloalkyl moiety, saturated or unsaturated, unsubstituted, mono- or polysubstituted; wherein said 3-12-membered heterocycloalkyl moiety is connected through —CH₂— or —CH₂CH₂—. More preferably, R⁴ means -oxetanyl, -tetrahydrofuranyl or -tetrahydropyranyl, in each case unsubstituted or substituted with one, two, three or four substituents independently of one another selected from the group consisting of —F, —Cl, —Br, —I, —CN, —OH, —C₁-C₄-alkyl, —O—C₁-C₄-alkyl, —C(═O)OH, —C(═O)OC₁-C₄-alkyl, —C(═O)NH₂, —C(═O)NHC₁-C₄-alkyl, —C(═O)N(C₁-C₄-alkyl)₂, —S(═O)C₁-C₄-alkyl and —S(═O)₂C₁-C₄-alkyl; wherein said -oxetanyl, -tetrahydrofuranyl or -tetrahydropyranyl is connected through —CH₂— or —CH₂CH₂—.

In yet another preferred embodiment of the compound according to the invention, R⁴ means a 6-14-membered aryl moiety, unsubstituted, mono- or polysubstituted; wherein said 6-14-membered aryl moiety is connected through —C₁-C₆-alkylene-, linear or branched, saturated or unsaturated, unsubstituted, mono- or polysubstituted. Preferably, R⁴ means -phenyl, unsubstituted, mono- or polysubstituted; wherein said -phenyl is connected through —CH₂— or —CH₂CH₂—. More preferably, R⁴ means -phenyl, unsubstituted or substituted with one, two, three or four substituents independently of one another selected from the group consisting of —F, —Cl, —Br, —I, —CN, —OH, —C₁-C₄-alkyl, —O—C₁-C₄-alkyl, —C(═O)OH, —C(═O)OC₁-C₄-alkyl, —C(═O)NH₂, —C(═O)NHC₁-C₄-alkyl, —C(═O)N(C₁-C₄-alkyl)₂, —S(═O)C₁-C₄-alkyl and —S(═O)₂C₁-C₄-alkyl; wherein said -phenyl is connected through —CH₂— or —CH₂CH₂—.

In a further preferred embodiment of the compound according to the invention, R⁴ means a 5-14-membered heteroaryl moiety, unsubstituted, mono- or polysubstituted; wherein said 5-14-membered heteroaryl moiety is connected through —C₁-C₆-alkylene-, linear or branched, saturated or unsaturated, unsubstituted, mono- or polysubstituted. Preferably, R⁴ means a 5-14-membered heteroaryl moiety, unsubstituted, mono- or polysubstituted; wherein said -phenyl is connected through —CH₂— or —CH₂CH₂—. More preferably, R⁴ means -pyridinyl, -pyrimidinyl, -pyrazinyl, or -pyrazolinyl, in each case unsubstituted or substituted with one, two, three or four substituents independently of one another selected from the group consisting of —F, —Cl, —Br, —I, —CN, —OH, —C₁-C₄-alkyl, —O—C₁-C₄-alkyl, —C(═O)OH, —C(═O)OC₁-C₄-alkyl, —C(═O)NH₂, —C(═O)NHC₁-C₄-alkyl, —C(═O)N(C₁-C₄-alkyl)₂, —S(═O)C₁-C₄-alkyl and —S(═O)₂C₁-C₄-alkyl; wherein said -pyridinyl, -pyrimidinyl, -pyrazinyl, or -pyrazolinyl is connected through —CH₂— or —CH₂CH₂—.

In a preferred embodiment of the compound according to the invention, R means -phenyl, unsubstituted, mono- or polysubstituted. Preferably, R⁵ means -phenyl unsubstituted or substituted with one, two, three or four substituents independently of one another selected from the group consisting of —F; —Cl; —Br; —I; —CN; —OH; —C₁-C₄-alkyl; —CF₃; -3-12-membered cycloalkyl, saturated or unsaturated, unsubstituted, mono- or polysubstituted; preferably -cyclopropyl, saturated, unsubstituted; -3-12-membered heterocycloalkyl, saturated or unsaturated, unsubstituted, mono- or polysubstituted; preferably -pyrrolidinyl, -piperidinyl, -morpholinyl, -piperazinyl, -thiomorpholinyl, or -thiomorpholinyl dioxide, in each case saturated, unsubstituted or monosubstituted with —C₁-C₄-alkyl; -6-14-membered aryl, unsubstituted, mono- or polysubstituted; preferably -phenyl, unsubstituted; —O—C₁-C₄-alkyl; —S—C₁-C₄-alkyl; —C(═O)OH; —C(═O)O—C₁-C₄-alkyl; —C(═O)NH₂; —C(═O)NHC₁-C₄-alkyl; —C(═O)N(C₁-C₄-alkyl)₂; —C(═O)N(C₁-C₄-alkyl)(C₁-C₄-alkyl-OH); —C(═O)NH—(CH₂)₁₋₃-3-12-membered cycloalkyl, saturated or unsaturated, unsubstituted or monosubstituted with —OH; preferably —C(═O)NH—(CH₂)₁₋₃-cyclobutyl, saturated or unsaturated, unsubstituted or monosubstituted with —OH; —C(═O)-3-12-membered heterocycloalkyl, saturated or unsaturated, unsubstituted, mono- or polysubstituted; preferably —C(═O)-morpholinyl, saturated, unsubstituted; —S(═O)C₁-C₄-alkyl; —S(═O)₂C₁-C₄-alkyl; and —S(═O)₂N(C₁-C₄-alkyl)₂.

In another preferred embodiment of the compound according to the invention, R⁵ means -1,2-benzodioxole, -pyrazinyl, -pyridazinyl, -pyridinyl, -pyrimidinyl, -thienyl, -imidazolyl, -benzimidazolyl, -thiazolyl, -1,3,4-thiadiazolyl, -benzothiazolyl, -oxazolyl, -benzoxazolyl, -pyrazolyl, -quinolinyl, -isoquinolinyl, -quinazolinyl, -indolyl, -indolinyl, -benzo[c][1,2,5]oxadiazolyl, -imidazo[1,2-a]pyrazinyl, or -1H-pyrrolo[2,3-b]pyridinyl, in each case unsubstituted, mono- or polysubstituted; preferably -pyrazinyl, -pyridazinyl, -pyridinyl, -pyrimidinyl, or -thienyl, in each case unsubstituted, mono- or polysubstituted. Preferably, R⁵ means -pyrazinyl, -pyridazinyl, -pyridinyl, -pyrimidinyl, or -thienyl, in each case unsubstituted or substituted with one, two, three or four substituents independently of one another selected from the group consisting of —F; —Cl; —Br; —I; —CN; —OH; —C₁-C₄-alkyl; —CF₃; -3-12-membered cycloalkyl, saturated or unsaturated, unsubstituted, mono- or polysubstituted; preferably -cyclopropyl, saturated, unsubstituted; -3-12-membered heterocycloalkyl, saturated or unsaturated, unsubstituted, mono- or polysubstituted; preferably -pyrrolidinyl, -piperidinyl, -morpholinyl, -piperazinyl, -thiomorpholinyl, or -thiomorpholinyl dioxide, in each case saturated, unsubstituted or monosubstituted with —C₁-C₄-alkyl; -6-14-membered aryl, unsubstituted, mono- or polysubstituted; preferably -phenyl, unsubstituted; —O—C₁-C₄-alkyl; —S—C₁-C₄-alkyl; —C(═O)OH; —C(═O)O—C₁-C₄-alkyl; —C(═O)NH₂; —C(═O)NHC₁-C₄-alkyl; —C(═O)N(C₁-C₄-alkyl)₂; —C(═O)N(C₁-C₄-alkyl)(C₁-C₄-alkyl-OH); —C(═O)NH—(CH₂)₁₋₃-3-12-membered cycloalkyl, saturated or unsaturated, unsubstituted or monosubstituted with —OH; preferably —C(═O)NH—(CH₂)₁₋₃-cyclobutyl, saturated or unsaturated, unsubstituted or monosubstituted with —OH; —C(═O)-3-12-membered heterocycloalkyl, saturated or unsaturated, unsubstituted, mono- or polysubstituted;

preferably —C(═O)-morpholinyl, saturated, unsubstituted; —S(═O)C₁-C₄-alkyl; —S(═O)₂C₁-C₄-alkyl; and —S(═O)₂N(C₁-C₄-alkyl)₂.

In still another preferred embodiment of the compound according to the invention, R⁵ means a bicyclic 9-10-membered heteroaryl moiety, unsubstituted, mono- or polysubstituted. Preferably, R⁵ means imidazo[1,2-a]pyrazine, unsubstituted or monosubstituted with —C₁-C₄-alkyl.

Preferably, R⁵ means -phenyl, -1,2-benzodioxole, -pyrazinyl, -pyridazinyl, -pyridinyl, -pyrimidinyl, -thienyl, -imidazolyl, -benzimidazolyl, -thiazolyl, -1,3,4-thiadiazolyl, -benzothiazolyl, -oxazolyl, -benzoxazolyl, -pyrazolyl, -quinolinyl, -isoquinolinyl, -quinazolinyl, -indolyl, -indolinyl, -benzo[c][1,2,5]oxadiazolyl, -imidazo[1,2-a]pyrazinyl, or -1H-pyrrolo[2,3-b]pyridinyl, in each case unsubstituted or substituted with one, two, three or four substituents independently of one another selected from the group consisting of

—F; —Cl; —Br; —I;

—CN; —C₁-C₄-alkyl; —CF₃; —C₁-C₄-alkyl-C(═O)NH₂; —C₁-C₄-alkyl-S(═O)₂—C₁-C₄-alkyl; —C(═O)—C₁-C₄-alkyl; —C(═O)OH; —C(═O)O—C₁-C₄-alkyl; —C(═O)NH₂; —C(═O)NHC₁-C₄-alkyl; —C(═O)N(C₁-C₄-alkyl)₂; —C(═O)NH(C₁-C₄-alkyl-OH); —C(═O)N(C₁-C₄-alkyl)(C₁-C₄-alkyl-OH); —C(═O)NH—(CH₂CH₂O)₁₋₃₀—CH₃; —NH₂; —NHC₁-C₄-alkyl; —N(C₁-C₄-alkyl)₂; —NHC₁-C₄-alkyl-OH; —NCH₃C₁-C₄-alkyl-OH; —NH—C₁-C₄-alkyl-C(═O)NH₂; —NCH₃—C₁-C₄-alkyl-C(═O)NH₂; —NHC(═O)—C₁-C₄-alkyl; —NCH₃C(═O)—C₁-C₄-alkyl; —OH; —O—C₁-C₄-alkyl; —OCF₃; —O—C₁-C₄-alkyl-CO₂H; —O—C₁-C₄-alkyl-C(═O)O—C₁-C₄-alkyl; —O—C₁-C₄-alkyl-CONH₂; —S—C₁-C₄-alkyl; —S(═O)C₁-C₄-alkyl; —S(═O)₂C₁-C₄-alkyl; and —S(═O)₂N(C₁-C₄-alkyl)₂; -3-12-membered cycloalkyl, saturated or unsaturated, unsubstituted, mono- or polysubstituted; wherein said 3-12-membered cycloalkyl is optionally connected through —CH₂—, —NH—, —NCH₃—, —NH—(CH₂)₁₋₃—, —NCH₃(CH₂)₁₋₃—, —(C═O)—, —NHC(═O)—, —NCH₃C(═O)—, —C(═O)NH—(CH₂)₁₋₃—, —C(═O)NCH₃—(CH₂)₁₋₃—; -3-12-membered heterocycloalkyl, saturated or unsaturated, unsubstituted, mono- or polysubstituted; wherein said 3-12-membered heterocycloalkyl is optionally connected through —CH₂—, —NH—, —NCH₃—, —NH—(CH₂)₁₋₃—, —NCH₃(CH₂)₁₋₃—, —(C═O)—, —NHC(═O)—, —NCH₃C(═O)—, —C(═O)NH—(CH₂)₁₋₃—, —C(═O)NCH₃—(CH₂)₁₋₃—; -6-14-membered aryl, unsubstituted, mono- or polysubstituted; wherein said 6-14-membered aryl is optionally connected through —CH₂—, —NH—, —NCH₃—, —NH—(CH₂)₁₋₃—, —NCH₃(CH₂)₁₋₃—, —(C═O)—, —NHC(═O)—, —NCH₃C(═O)—, —C(═O)NH—(CH₂)₁₋₃—, —C(═O)NCH₃—(CH₂)₁₋₃—; or -5-14-membered heteroaryl, unsubstituted, mono- or polysubstituted; wherein said 5-14-membered heteroaryl is optionally connected through —CH₂—, —NH—, —NCH₃—, —NH—(CH₂)₁₋₃—, —NCH₃(CH₂)₁₋₃—, —(C═O)—, —NHC(═O)—, —NCH₃C(═O)—, —C(═O)NH—(CH₂)₁₋₃—, —C(═O)NCH₃—(CH₂)₁₋₃—.

In preferred embodiments, the compound according to the invention has a structure according to any of general formulas (II-A) to (VIII-C):

wherein in each case R¹, R², R³, R⁴, and R⁵ are defined as above, R^(C) means —H, —OH, —F, —CN or —C₁-C₄-alkyl; preferably —H or —OH; R^(D) means —H or —F; or a physiologically acceptable salt thereof.

Preferably, in the compounds according to general formula (I) or any of the compounds according to general formulas (II-A) to (VIII-C), R⁵ is selected from the group consisting of:

In a particularly preferred embodiment of the compound according to the invention

R¹ means —H or —CH₃; R² means —C₁-C₆-alkyl, linear or branched, saturated, unsubstituted; cyclopropyl connected through —CH₂—; or tetrahydropyranyl connected through —CH₂—; R³ means -phenyl, benzyl, -thienyl or -pyridinyl, in each case unsubstituted or substituted with one, two, three or four substituents independently of one another selected from the group consisting of —F, —Cl, —CN, —CH₃, —CH₂CH₃, —CH₂F, —CHF₂, —CF₃, —OCF₃, —OH, —OCH₃, —C(═O)NH₂, C(═O)NHCH₃, —C(═O)N(CH₃)₂, —NH₂, —NHCH₃, —N(CH₃)₂, —NHC(═O)CH₃, —CH₂OH, SOCH₃ and SO₂CH₃; or R⁴ means

—H;

—C₁-C₆-alkyl, linear or branched, saturated, unsubstituted or substituted with one, two, three or four substituents independently of one another selected from the group consisting of —F, —Cl, —Br, —I, —CN, —OH, —O—C₁-C₄-alkyl, —C(═O)NH—C₁-C₆-alkyl, —C(═O)N(C₁-C₆-alkyl)₂ or —C(═O)NRR′ wherein R and R′ together with the nitrogen atom to which they are attached form a ring and mean —(CH₂)₃₋₅—; 3-6-membered cycloalkyl, unsubstituted or substituted with one, two, three or four substituents independently of one another selected from the group consisting of —F, —Cl, —Br, —I, —CN, —OH, and —O—C₁-C₄-alkyl, wherein said 3-6-membered cycloalkyl is connected through —C₁-C₆-alkylene; 3-6-membered heterocycloalkyl, unsubstituted or substituted with one, two, three or four substituents independently of one another selected from the group consisting of —F, —Cl, —Br, —I, —CN, —OH, and —O—C₁-C₄-alkyl, wherein said 3-6-membered heterocycloalkyl is connected through —C₁-C₆-alkylene; -phenyl, unsubstituted or monosubstituted with —OCH₃; wherein said -phenyl is connected through —C₁-C₆-alkylene-; or -pyridyl, unsubstituted, mono- or polysubstituted; wherein said -pyridyl is connected through —C₁-C₆-alkylene-; R⁵ means -phenyl, -1,2-benzodioxole, -pyrazinyl, -pyridazinyl, -pyridinyl, -pyrimidinyl, -thienyl, -imidazolyl, -benzimidazolyl, -thiazolyl, -1,3,4-thiadiazolyl, -benzothiazolyl, -oxazolyl, -benzoxazolyl, -pyrazolyl, -quinolinyl, -isoquinolinyl, -quinazolinyl, -indolyl, -indolinyl, -benzo[c][1,2,5]oxadiazolyl, -imidazo[1,2-a]pyrazinyl, or -1H-pyrrolo[2,3-b]pyridinyl, in each case unsubstituted or substituted with one, two, three or four substituents independently of one another selected from the group consisting of

-   -   —F; —Cl; —Br; —I;     -   —CN; —C₁-C₄-alkyl; —C₁-C₄-alkyl-OH; —CF₃; —C₁-C₄-alkyl-CF₃;         —C₁-C₄-alkyl-C(═O)NH₂; —C₁-C₄-alkyl-C(═O)NHC₁-C₆-alkyl;         —C₁-C₄-alkyl-C(═O)N(C₁-C₆-alkyl)₂;         —C₁-C₄-alkyl-S(═O)₂—C₁-C₄-alkyl;     -   —C(═O)—C₁-C₄-alkyl; —C(═O)OH; —C(═O)O—C₁-C₄-alkyl; —C(═O)NH₂;         —C(═O)NHC₁-C₄-alkyl; —C(═O)N(C₁-C₄-alkyl)₂;         —C(═O)NH(C₁-C₄-alkyl-OH); —C(═O)N(C₁-C₄-alkyl)(C₁-C₄-alkyl-OH);         —C(═O)NH—(CH₂CH₂O)₁₋₃₀—CH₃;     -   —NH₂; —NHC₁-C₄-alkyl; —N(C₁-C₄-alkyl)₂; —NHC₁-C₄-alkyl-OH;         —NCH₃C₁-C₄-alkyl-OH; —NH—C₁-C₄-alkyl-C(═O)NH₂;         —NCH₃—C₁-C₄-alkyl-C(═O)NH₂; —NHC(═O)—C₁-C₄-alkyl;         —NCH₃C(═O)—C₁-C₄-alkyl;     -   —OH; —O—C₁-C₄-alkyl; —OCF₃; —O—C₁-C₄-alkyl-CO₂H;         —O—C₁-C₄-alkyl-C(═O)O—C₁-C₄-alkyl; —O—C₁-C₄-alkyl-CONH₂;     -   —S—C₁-C₄-alkyl; —S(═O)C₁-C₄-alkyl; —S(═O)₂C₁-C₄-alkyl; and         —S(═O)₂N(C₁-C₄-alkyl)₂;     -   -3-12-membered cycloalkyl, saturated or unsaturated,         unsubstituted, mono- or polysubstituted; wherein said         3-12-membered cycloalkyl is optionally connected through —CH₂—,         —O—, —NH—, —NCH₃—, —NH—(CH₂)₁₋₃—, —NCH₃(CH₂)₁₋₃—, —(C═O)—,         —NHC(═O)—, —NCH₃C(═O)—, —C(═O)NH—(CH₂)₁₋₃—,         —C(═O)NCH₃—(CH₂)₁₋₃—;     -   -3-12-membered heterocycloalkyl, saturated or unsaturated,         unsubstituted, mono- or polysubstituted; wherein said         3-12-membered heterocycloalkyl is optionally connected through         —CH₂—, —O—, —NH—, —NCH₃—, —NH—(CH₂)₁₋₃—, —NCH₃(CH₂)₁₋₃—,         —(C═O)—, —NHC(═O)—, —NCH₃C(═O)—, —C(═O)NH—(CH₂)₁₋₃—,         —C(═O)NCH₃—(CH₂)₁₋₃—;     -   -6-14-membered aryl, unsubstituted, mono- or polysubstituted;         wherein said 6-14-membered aryl is optionally connected through         —CH₂—, —O—, —NH—, —NCH₃—, —NH—(CH₂)₁₋₃—, —NCH₃(CH₂)₁₋₃—,         —(C═O)—, —NHC(═O)—, —NCH₃C(═O)—, —C(═O)NH—(CH₂)₁₋₃—,         —C(═O)NCH₃—(CH₂)₁₋₃—; or     -   -5-14-membered heteroaryl, unsubstituted, mono- or         polysubstituted; wherein said 5-14-membered heteroaryl is         optionally connected through —CH₂—, —O—, —NH—, —NCH₃—,         —NH—(CH₂)₁₋₃—, —NCH₃(CH₂)₁₋₃—, —(C═O)—, —NHC(═O)—, —NCH₃C(═O)—,         —C(═O)NH—(CH₂)₁₋₃—, —C(═O)NCH₃—(CH₂)₁₋₃—; and         R¹¹, R¹², R¹³, R¹⁴, R¹⁵, R¹⁶, R¹⁷, R¹⁸, R¹⁹, and R²⁰ mean —H.

In a particularly preferred embodiment of the compound according to the invention

R¹ means —H or —CH₃; and/or R² means —C₁-C₆-alkyl, linear or branched, saturated, unsubstituted; preferably, R² means —CH₃ or —CH₂CH₃; more preferably, R¹ and R² both mean —CH₃; and/or R³ means -phenyl, -thienyl or -pyridinyl, in each case unsubstituted or substituted with one, two, three or four substituents independently of one another selected from the group consisting of —F, —Cl, —CN, —CH₃, —CH₂CH₃, —CH₂F, —CHF₂, —CF₃, —OCF₃, —OH, —OCH₃, —C(═O)NH₂, C(═O)NHCH₃, —C(═O)N(CH₃)₂, —NH₂, —NHCH₃, —N(CH₃)₂, —NHC(═O)CH₃, —CH₂OH, SOCH₃ and SO₂CH₃; preferably, R³ means -phenyl, -thienyl or -pyridinyl, in each case unsubstituted or substituted with —F; more preferably, R³ means phenyl, unsubstituted; and/or R⁴ means

—H;

—C₁-C₆-alkyl, linear or branched, saturated, unsubstituted or substituted with one, two, three or four substituents independently of one another selected from the group consisting of —F, —Cl, —Br, —I, —CN, —OH, and —O—C₁-C₄-alkyl; or 3-6-membered cycloalkyl, unsubstituted or substituted with one, two, three or four substituents independently of one another selected from the group consisting of —F, —Cl, —Br, —I, —CN, —OH, and —O—C₁-C₄-alkyl, wherein said 3-6-membered cycloalkyl is connected through —C₁-C₆-alkylene; preferably, R⁴ means 3-6-membered cycloalkyl, unsubstituted or substituted with one, two, three or four substituents independently of one another selected from the group consisting of —F, —Cl, —Br, —I, —CN, —OH, and —O—C₁-C₄-alkyl, wherein said 3-6-membered cycloalkyl is connected through —CH₂— or —CH₂CH₂—; more preferably, R⁴ means -cyclobutyl, unsubstituted or monosubstituted with —OH, wherein said -cyclobutyl is connected through —CH₂—; and/or R⁵ means -phenyl, -pyrazinyl, -pyridazinyl, -pyridinyl, -pyrimidinyl, -thienyl, or imidazo[1,2-a]pyrazine, in each case unsubstituted or substituted with one, two, three or four substituents independently of one another selected from the group consisting of —F; —Cl; —Br; —I; —CN; —OH; —C₁-C₄-alkyl; —CF₃; -3-12-membered cycloalkyl, saturated or unsaturated, unsubstituted, mono- or polysubstituted; preferably cyclopropyl, saturated, unsubstituted; -3-12-membered heterocycloalkyl, saturated or unsaturated, unsubstituted, mono- or polysubstituted; preferably -pyrrolidinyl, -morpholinyl, -piperazinyl, -thiomorpholinyl, or -thiomorpholinyl dioxide, in each case saturated, unsubstituted or monosubstituted with —C₁-C₄-alkyl; -6-14-membered aryl, unsubstituted, mono- or polysubstituted; preferably -phenyl, unsubstituted; —O—C₁-C₄-alkyl; —S—C₁-C₄-alkyl; —C(═O)OH; —C(═O)O—C₁-C₄-alkyl; —C(═O)NH₂; —C(═O)NHC₁-C₄-alkyl; —C(═O)N(C₁-C₄-alkyl)₂; —C(═O)N(C₁-C₄-alkyl)(C₁-C₄-alkyl-OH); —C(═O)NH—(CH₂)₁₋₃-3-12-membered cycloalkyl, saturated or unsaturated, unsubstituted or monosubstituted with —OH; preferably —C(═O)NH—(CH₂)₁₋₃-cyclobutyl, saturated or unsaturated, unsubstituted or monosubstituted with —OH; —C(═O)-3-12-membered heterocycloalkyl, saturated or unsaturated, unsubstituted, mono- or polysubstituted; preferably —C(═O)-morpholinyl, saturated, unsubstituted; —S(═O)C₁-C₄-alkyl; —S(═O)₂C₁-C₄-alkyl; and —S(═O)₂N(C₁-C₄-alkyl)₂; and/or R¹¹, R¹², R¹³, R¹⁴, R¹⁵, R¹⁶, R¹⁷, R¹⁸, R¹⁹, and R²⁰ mean —H.

Preferably, the compound according to the invention is selected from the group consisting of

SC_3001 cis-5-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3- diazaspiro[4.5]decan-3-yl]-pyrimidine-2-carbonitrile SC_3002 cis-5-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3- diazaspiro[4.5]decan-3-yl]-pyrazine-2-carbonitrile SC_3003 cis-5-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3- diazaspiro[4.5]decan-3-yl]-4-methoxy-pyrimidine-2-carbonitrile SC_3004 cis-5-[8-Dimethylamino-1-(2-methoxy-ethyl)-2-oxo-8-phenyl-1,3- diazaspiro[4.5]decan-3-yl]-pyrimidine-2-carbonitrile SC_3005 cis-5-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3- diazaspiro[4.5]decan-3-yl]-pyrimidine-2-carboxylic acid amide SC_3006 cis-5-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3- diazaspiro[4.5]decan-3-yl]-2-methylsulfonyl-pyrimidine-4-carbonitrile SC_3007 cis-5-[1-(2-Methoxy-ethyl)-8-methylamino-2-oxo-8-phenyl-1,3- diazaspiro[4.5]decan-3-yl]-pyrimidine-2-carbonitrile SC_3008 cis-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3- diazaspiro[4.5]decan-3-yl]-5-methylsulfonyl-benzonitrile SC_3009 cis-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3- diazaspiro[4.5]decan-3-yl]-benzamide SC_3010 cis-3-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3- diazaspiro[4.5]decan-3-yl]-benzamide SC_3011 cis-5-[8-Dimethylamino-1-[(1-hydroxy-cyclobutyl)-methyl]-2-oxo-8-phenyl-1,3- diazaspiro[4.5]decan-3-yl]-pyrimidine-2-carboxylic acid amide SC_3012 cis-5-[1-(Cyclobutyl-methyl)-8-methylamino-2-oxo-8-phenyl-1,3- diazaspiro[4.5]decan-3-yl]-4-methoxy-pyrimidine-2-carbonitrile SC_3013 cis-5-[8-Dimethylamino-1-[(1-hydroxy-cyclobutyl)-methyl]-2-oxo-8-phenyl-1,3- diazaspiro[4.5]decan-3-yl]-pyrimidine-2-carbonitrile SC_3014 cis-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3- diazaspiro[4.5]decan-3-yl]-pyrimidine-5-carbonitrile SC_3015 cis-5-[8-Dimethylamino-1-[(1-hydroxy-cyclobutyl)-methyl]-3-(2-methoxy-pyrimidin- 5-yl)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one SC_3016 cis-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3- diazaspiro[4.5]decan-3-yl]-pyrimidine-5-carboxylic acid amide SC_3017 cis-4-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3- diazaspiro[4.5]decan-3-yl]-N-methyl-benzamide SC_3018 cis-5-(8-Dimethylamino-2-oxo-8-phenyl-1-propyl-1,3-diazaspiro[4.5]decan-3-yl)- pyrimidine-2-carbonitrile SC_3019 cis-5-[8-Dimethylamino-1-(3-methoxy-propyl)-2-oxo-8-phenyl-1,3- diazaspiro[4.5]decan-3-yl]-pyrimidine-2-carbonitrile SC_3020 cis-5-[1-(Cyclopropyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3- diazaspiro[4.5]decan-3-yl]-pyrimidine-2-carbonitrile SC_3021 cis-4-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3- diazaspiro[4.5]decan-3-yl]-benzamide SC_3022 cis-1-(Cyclobutyl-methyl)-8-dimethylamino-8-phenyl-3-[2-(trifluoromethyl)- pyrimidin-5-yl]-1,3-diazaspiro[4.51decan-2-one SC_3023 cis-8-Dimethylamino-1-[(1-hydroxy-cyclobutyl)-methyl]-3-(2-hydroxy-pyrimidin- 5-yl)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one SC_3024 cis-5-[8-Dimethylamino-1-(2-methyl-propyl)-2-oxo-8-phenyl-1,3- diazaspiro[4.5]decan-3-yl]-pyrimidine-2-carbonitrile SC_3025 cis-5-[8-Dimethylamino-1-(2-hydroxy-ethyl)-2-oxo-8-phenyl-1,3- diazaspiro[4.5]decan-3-yl]-pyrimidine-2-carbonitrile SC_3026 cis-5-[1-(Cyclobutyl-methyl)-8-methylamino-2-oxo-8-phenyl-1,3- diazaspiro[4.5]decan-3-yl]-4-methyl-pyridine-2-carbonitrile SC_3027 cis-1-(Cyclobutyl-methyl)-3-(5-methoxy-pyrazin-2-yl)-8-methylamino-8-phenyl- 1,3-diazaspiro[4.5]decan-2-one SC_3028 cis-4-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3- diazaspiro[4.5]decan-3-yl]-N,N-dimethyl-benzamide SC_3029 cis-4-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3- diazaspiro[4.5]decan-3-yl]-N-ethyl-N-(2-hydroxy-ethyl)-benzamide SC_3030 cis-2-[1-(Cyclobutyl-methyl)-8-methylamino-2-oxo-8-phenyl-1,3- diazaspiro[4.5]decan-3-yl]-5-methylsulfonyl-benzonitrile SC_3031 cis-1-(Cyclobutyl-methyl)-8-methylamino-3-[2-methylsulfonyl-4- (trifluoromethyl)-phenyl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one SC_3032 cis-4-[1-(Cyclobutyl-methyl)-8-methylamino-2-oxo-8-phenyl-1,3- diazaspiro[4.5]decan-3-yl]-N,N-dimethyl-3-(trifluoromethyl)-benzenesulfonic acid amide SC_3033 cis-4-[1-(Cyclobutyl-methyl)-8-(ethyl-methyl-amino)-2-oxo-8-phenyl-1,3- diazaspiro[4.5]decan-3-yl]-benzonitrile SC_3034 cis-1-(Cyclobutyl-methyl)-8-(ethyl-methyl-amino)-8-phenyl-3-[2- (trifluoromethyl)-pyrimidin-5-yl]-1,3-diazaspiro[4.5]decan-2-one SC_3035 cis-5-[1-(Cyclobutyl-methyl)-8-(ethyl-methyl-amino)-2-oxo-8-phenyl-1,3- diazaspiro[4.5]decan-3-yl]-pyrimidine-2-carbonitrile SC_3036 cis-5-[8-Dimethylamino-1-](1-methyl-cyclobutyl)-methyl]-2-oxo-8-phenyl-1,3- diazaspiro[4.5]decan-3-yl]-pyrimidine-2-carbonitrile SC_3037 cis-2-[3-(2-Cyano-pyrimidin-5-yl)-8-dimethylamino-2-oxo-8-phenyl-1,3- diazaspiro[4.5]decan-1-yl]-N,N-dimethyl-acetamide SC_3038 cis-1-(Cyclobutyl-methyl)-8-methylamino-8-phenyl-3-[2-(trifluoromethyl)- pyrimidin-5-yl]-1,3-diazaspiro[4.5]decan-2-one SC_3039 cis-5-[8-Dimethylamino-8-(3-fluorophenyl)-1-(4-methoxy-butyl)-2-oxo-1,3- diazaspiro[4.5]decan-3-yl]-pyrimidine-2-carbonitrile SC_3040 cis-5-[8-Dimethylamino-1-(3-methoxy-propyl)-2-oxo-8-phenyl-1,3- diazaspiro[4.5]decan-3-yl]-4-methoxy-pyrimidine-2-carbonitrile SC_3041 cis-5-[1-[(1-Cyano-cyclobutyl)-methyl]-8-dimethylamino-2-oxo-8-phenyl-1,3- diazaspiro[4.5]decan-3-yl]-pyrimidine-2-carbonitrile SC_3042 cis-N-(Cyclobutyl-methyl)-5-[1-(cyclobutyl-methyl)-8-dimethylamino-8-(3- fluorophenyl)-2-oxo-1,3-diazaspiro[4.5]decan-3-yl]-pyrimidine-2-carboxylic acid amide SC_3043 cis-5-[1-(3-Methoxy-propyl)-8-methylamino-2-oxo-8-phenyl-1,3- diazaspiro[4.5]decan-3-yl]-pyrimidine-2-carbonitrile SC_3044 cis-5-[8-Dimethylamino-8-(3-fluorophenyl)-1-methyl-2-oxo-1,3- diazaspiro[4.5]decan-3-yl]-pyrimidine-2-carbonitrile SC_3045 cis-4-Methoxy-5-[1-(3-methoxy-propyl)-8-methylamino-2-oxo-8-phenyl-1,3- diazaspiro[4.5]decan-3-yl]-pyrimidine-2-carbonitrile SC_3046 cis-4-[8-Dimethylamino-1-(2-methoxy-ethyl)-2-oxo-8-phenyl-1,3- diazaspiro[4.5]decan-3-yl]-pyrimidine-2-carbonitrile SC_3047 cis-5-[8-Dimethylamino-1-(2-methoxy-ethyl)-2-oxo-8-phenyl-1,3- diazaspiro[4.5]decan-3-yl]-4-methoxy-pyrimidine-2-carbonitrile SC_3048 cis-4-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3- diazaspiro[4.5]decan-3-yl]-pyrimidine-2-carbonitrile SC_3049 cis-1-(Cyclobutyl-methyl)-8-dimethylamino-3-(6-methylsulfanyl-pyrimidin-4-yl)- 8-phenyl-1,3-diazaspiro[4.5]decan-2-one SC_3050 cis-2-[3-(2-Cyano-pyrimidin-4-yl)-8-dimethylamino-2-oxo-8-phenyl-1,3- diazaspiro[4.5]decan-1-yl]-N,N-dimethyl-acetamide SC_3051 cis-6-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3- diazaspiro[4.5]decan-3-yl]-pyrimidine-4-carbonitrile SC_3052 cis-2-(8-Dimethylamino-2-oxo-3,8-diphenyl-1,3-diazaspiro[4.5]decan-1-yl)-N,N- dimethyl-acetamide SC_3053 cis-1-(Cyclobutyl-methyl)-8-dimethylamino-3,8-diphenyl-1,3- diazaspiro[4.5]decan-2-one SC_3054 cis-2-[8-Dimethylamino-1-(2-methoxy-ethyl)-2-oxo-8-phenyl-1,3- diazaspiro[4.5]decan-3-yl]-pyrimidine-5-carbonitrile SC_3055 cis-8-Dimethylamino-1-(2-methoxy-ethyl)-3,8-diphenyl-1,3-diazaspiro[4.5]decan- 2-one SC_3056 cis-5-[8-Dimethylamino-1-(2-methoxy-ethyl)-2-oxo-8-phenyl-1,3- diazaspiro[4.5]decan-3-yl]-4-methyl-pyridine-2-carbonitrile SC_3057 cis-N,N-Dimethyl-2-(8-methylamino-2-oxo-3,8-diphenyl-1,3-diazaspiro[4.5]decan- 1-yl)-acetamide SC_3058 cis-5-[1-[(1-Cyano-cyclobutyl)-methyl]-8-methylamino-2-oxo-8-phenyl-1,3- diazaspiro[4.5]decan-3-yl]-pyrimidine-2-carbonitrile SC_3059 cis-5-[1-[(1-Cyano-cyclobutyl)-methyl]-8-(ethyl-methyl-amino)-2-oxo-8-phenyl- 1,3-diazaspiro[4.5]decan-3-yl]-pyrimidine-2-carbonitrile SC_3060 cis-4-[8-Dimethylamino-1-[(1-hydroxy-cyclobutyl)-methyl]-2-oxo-8-phenyl-1,3- diazaspiro[4.5]decan-3-yl]-benzonitrile SC_3061 cis-3-[8-Dimethylamino-1-[(1-hydroxy-cyclobutyl)-methyl]-2-oxo-8-phenyl-1,3- diazaspiro[4.5]decan-3-yl]-benzonitrile SC_3063 cis-5-[1-[(1-Cyano-cyclobutyl)-methyl]-8-dimethylamino-2-oxo-8-phenyl-1,3- diazaspiro[4.5]decan-3-yl]-pyridine-2-carbonitrile SC_3064 cis-2-[3-(2-Cyano-pyrimidin-5-yl)-8-dimethylamino-2-oxo-8-phenyl-1,3- diazaspiro[4.5]decan-1-yl]-N-propyl-acetamide SC_3065 cis-5-[1-(Cyclobutyl-methyl)-8-(ethyl-methyl-amino)-2-oxo-8-phenyl-1,3- diazaspiro[4.5]decan-3-yl]-4-methoxy-pyrimidine-2-carbonitrile SC_3066 cis-4-[1-(Cyclobutyl-methyl)-8-methylamino-2-oxo-8-phenyl-1,3- diazaspiro[4.5]decan-3-yl]-3-methoxy-benzonitrile SC_3067 cis-5-[8-Dimethylamino-1-(3-methoxy-propyl)-2-oxo-8-phenyl-1,3- diazaspiro[4.5]decan-3-yl]-6-methoxy-pyridine-2-carbonitrile SC_3068 cis-4-[8-Dimethylamino-1-[(1-hydroxy-cyclobutyl)-methyl]-2-oxo-8-phenyl-1,3- diazaspiro[4.5]decan-3-yl]-benzamide SC_3069 cis-5-[8-Dimethylamino-1-[(1-hydroxy-cyclobutyl)-methyl]-2-oxo-8-phenyl-1,3- diazaspiro[4.5]decan-3-yl]-pyridine-2-carbonitrile SC_3070 cis-5-[8-Dimethylamino-1-[(1-hydroxy-cyclobutyl)-methyl]-2-oxo-8-phenyl-1,3- diazaspiro[4.5]decan-3-yl]-N-[(1-hydroxy-cyclobutyl)-methyl]-pyridine-2- carboxylic acid amide SC_3071 cis-2-[8-Dimethylamino-1-[(1-hydroxy-cyclobutyl)-methyl]-2-oxo-8-phenyl-1,3- diazaspiro[4.5]decan-3-yl]-benzonitrile SC_3072 cis-3-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3- diazaspiro[4.5]decan-3-yl]-benzonitrile SC_3073 cis-1-(Cyclobutyl-methyl)-8-dimethylamino-8-phenyl-3-[2-(trifluoromethyl)- pyrimidin-5-yl]-1,3-diazaspiro[4.5]decan-2-one SC_3074 cis-5-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3- diazaspiro[4.5]decan-3-yl]-4-methyl-pyridine-2-carboxylic acid methyl ester SC_3075 cis-1-(Cyclobutyl-methyl)-8-dimethylamino-3-(5-methoxy-pyrazin-2-yl)-8-phenyl- 1,3-diazaspiro[4.5]decan-2-one SC_3076 cis-1-(Cyclobutyl-methyl)-8-dimethylamino-3-(2-methoxy-pyrimidin-5-yl)-8- phenyl-1,3-diazaspiro[4.5]decan-2-one SC_3077 cis-4-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3- diazaspiro[4.5]decan-3-yl]-benzonitrile SC_3078 cis-5-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3- diazaspiro[4.5]decan-3-yl]-4-methyl-pyridine-2-carbonitrile SC_3079 cis-1-(Cyclobutyl-methyl)-8-dimethylamino-3-(5-fluoro-pyrimidin-2-yl)-8-phenyl- 1,3-diazaspiro[4.5]decan-2-one SC_3080 cis-4-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3- diazaspiro[4.5]decan-3-yl]-3-methoxy-benzonitrile SC_3081 cis-4-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3- diazaspiro[4.5]decan-3-yl]-benzoic acid methyl ester SC_3082 cis-1-(Cyclobutyl-methyl)-8-dimethylamino-8-phenyl-3-(2-pyrrolidin-1-yl- pyrimidin-4-yl)-1,3-diazaspiro[4.5]decan-2-one SC_3083 cis-1-(Cyclobutyl-methyl)-8-dimethylamino-8-phenyl-3-(5-pyridin-2-yl-thiophen- 2-yl)-1,3-diazaspiro[4.5]decan-2-one SC_3084 cis-1-(Cyclobutyl-methyl)-8-dimethylamino-3-[2-methylsulfonyl-4- (trifluoromethyl)-phenyl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one SC_3085 cis-1-(Cyclobutyl-methyl)-8-dimethylamino-8-phenyl-3-[6-(trifluoromethyl)- pyridin-3-yl]-1,3-diazaspiro[4.5]decan-2-one SC_3086 cis-1-(Cyclobutyl-methyl)-3-(2,4-dimethoxy-phenyl)-8-dimethylamino-8-phenyl- 1,3-diazaspiro[4.5]decan-2-one SC_3087 cis-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3- diazaspiro[4.5]decan-3-yl]-4-methylsulfonyl-benzonitrile SC_3088 cis-5-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3- diazaspiro[4.5]decan-3-yl]-2-fluoro-benzonitrile SC_3089 cis-4-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3- diazaspiro[4.5]decan-3-yl]-N,N-dimethyl-3-(trifluoromethyl)-benzenesulfonic acid amide SC_3090 cis-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3- diazaspiro[4.5]decan-3-yl]-benzonitrile SC_3091 cis-1-(Cyclobutyl-methyl)-8-dimethylamino-3-(2-methyl-imidazo[1,2-a]pyrazin-6- yl)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one SC_3092 cis-1-(Cyclobutyl-methyl)-8-dimethylamino-3-(4-methylsulfonyl-phenyl)-8- phenyl-1,3-diazaspiro[4.5]decan-2-one SC_3093 cis-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3- diazaspiro[4.5]decan-3-yl]-5-methoxy-benzonitrile SC_3094 cis-1-(Cyclobutyl-methyl)-8-dimethylamino-3,8-diphenyl-1,3- diazaspiro[4.5]decan-2-one SC_3096 cis-1-(Cyclobutyl-methyl)-8-dimethylamino-8-phenyl-3-pyrazin-2-yl-1,3- diazaspiro[4.5]decan-2-one SC_3097 cis-8-Dimethylamino-1-[(1-hydroxy-cyclobutyl)-methyl]-3-(2-morpholin-4-yl- pyrimidin-5-yl)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one SC_3098 cis-8-Dimethylamino-1-[(1-hydroxy-cyclobutyl)-methyl]-3-[2-(4-methyl-piperazin- 1-yl)-pyrimidin-5-yl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one SC_3099 cis-1-[(1-Hydroxy-cyclobutyl)-methyl]-8-methylamino-3-(2-morpholin-4-yl- pyrimidin-5-yl)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one SC_3100 cis-8-Dimethylamino-1-[(1-hydroxy-cyclobutyl)-methyl]-8-phenyl-3-(2-piperazin- 1-yl-pyrimidin-5-yl)-1,3-diazaspiro[4.5]decan-2-one hydrochloride SC_3101 cis-1-[(1-Hydroxy-cyclobutyl1)-methyl]-8-methylamino-3-[2-(4-methyl-piperazin- 1-yl)-pyrimidin-5-yl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one SC_3102 cis-1-[(1-Hydroxy-cyclobutyl)-methyl]-8-methylamino-8-phenyl-3-(2-piperazin-1- yl-pyrimidin-5-yl)-1,3-diazaspiro[4.5]decan-2-one dihydrochloride SC_3103 cis-1-(Cyclobutyl-methyl)-8-dimethylamino-3-[4-methyl-6-(trifluoromethyl)- pyridin-3-yl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one SC_3104 cis-1-(Cyclobutyl-methyl)-8-methylamino-3-[4-methyl-6-(trifluoromethyl)-pyridin- 3-yl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one SC_3105 cis-1-(Cyclopropyl-methyl)-8-dimethylamino-3-(4-methylsulfonyl-phenyl)-8- phenyl-1,3-diazaspiro[4.5]decan-2-one SC_3106 cis-1-(Cyclopropyl-methyl)-8-methylamino-3-(4-methylsulfonyl-phenyl)-8-phenyl- 1,3-diazaspiro[4.5]decan-2-one SC_3107 cis-1-(Cyclopropyl-methyl)-8-dimethylamino-3-(2-fluoro-4-methylsulfonyl- phenyl)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one SC_3108 cis-2-[8-Dimethylamino-1-[(1-hydroxy-cyclobutyl)-methyl]-2-oxo-8-phenyl-1,3- diazaspiro[4.5]decan-3-yl]-benzamide; formic acid SC_3109 cis-2-[8-Dimethylamino-1-[2-(1-methoxy-cyclobutyl)-ethyl]-2-oxo-8-phenyl-1,3- diazaspiro[4.5]decan-3-yl]-benzamide SC_3110 cis-8-Dimethylamino-1-[2-(1-methoxy-cyclobutyl)-ethyl]-3-(2-methyl-pyrimidin- 5-yl)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one SC_3111 cis-5-[1-[(1-Hydroxy-cyclobutyl)-methyl]-8-methylamino-2-oxo-8-phenyl-1,3- diazaspiro[4.5]decan-3-yl]-pyrimidine-2-carbonitrile SC_3112 cis-2-[1-[(1-Hydroxy-cyclobutyl)-methyl]-8-methylamino-2-oxo-8-phenyl-1,3- diazaspiro[4.5]decan-3-yl]-benzonitrile SC_3113 cis-4-[1-[(1-Hydroxy-cyclobutyl)-methyl]-8-methylamino-2-oxo-8-phenyl-1,3- diazaspiro[4.5]decan-3-yl]-3-methoxy-benzonitrile SC_3114 cis-4-[8-Ethylamino-1-[(1-hydroxy-cyclobutyl)-methyl]-2-oxo-8-phenyl-1,3- diazaspiro[4.5]decan-3-yl]-3-methoxy-benzonitrile SC_3115 cis-2-[8-Ethylamino-1-[(1-hydroxy-cyclobutyl)-methyl]-2-oxo-8-phenyl-1,3- diazaspiro[4.5]decan-3-yl]-benzonitrile SC_3116 cis-5-[1-[(1-Hydroxy-cyclobutyl)-methyl]-8-methylamino-2-oxo-8-phenyl-1,3- diazaspiro[4.5]decan-3-yl]-4-methoxy-pyrimidine-2-carbonitrile SC_3117 cis-2-[8-Dimethylamino-1-(oxetan-3-yl-methyl)-2-oxo-8-phenyl-1,3- diazaspiro[4.5]decan-3-yl]-benzamide SC_3118 cis-4-Methoxy-5-(8-methylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)- pyrimidine-2-carbonitrile SC_3119 cis-2-(8-Methylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)-benzamide SC_3120 cis-8-Dimethylamino-3-[2-(3-oxo-piperazin-1-yl)-pyrimidin-5-yl]-8-phenyl-1,3- diazaspiro[4.5]decan-2-one SC_3121 cis-3-(2-Cyclopropyl-pyrimidin-5-yl)-8-dimethylamino-8-phenyl-1,3- diazaspiro[4.5]decan-2-one SC_3122 cis-8-Dimethylamino-3-[4-methyl-6-(trifluoromethyl)-pyridin-3-yl]-8-phenyl-1,3- diazaspiro[4.5]decan-2-one SC_3123 cis-8-Dimethylamino-3-(2-methylsulfonyl-phenyl)-8-phenyl-1,3- diazaspiro[4.5]decan-2-one SC_3124 cis-8-Dimethylamino-8-phenyl-3-(2-piperazin-1-yl-pyrimidin-5-yl)-1,3- diazaspiro[4.5]decan-2-one SC_3125 trans-2-(8-Ethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)-benzamide SC_3126 cis--2-(8-Ethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)-benzamide SC_3127 cis-2-(8-Ethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)-benzamide SC_3128 cis-2-(8-Ethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)-benzamide SC_3129 cis-3-[5-(8-Dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)- pyrimidin-2-yl]-benzonitrile SC_3130 cis-8-Dimethylamino-3-[2-(4-methylsulfonyl-piperazin-1-yl)-pyrimidin-5-yl]-8- phenyl-1,3-diazaspiro[4.5]decan-2-one SC_3131 cis-3-[5-(8-Dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)- pyrimidin-2-yl]-benzamide SC_3132 cis-8-[(Cyclopropyl-methyl)-methyl-amino]-8-phenyl-3-[2-(trifluoromethyl)- pyrimidin-5-yl]-1,3-diazaspiro[4.5]decan-2-one SC_3133 cis-8-Dimethylamino-3-[2-(4-methyl-piperazine-1-carbonyl)-pyrimidin-5-yl]-8- phenyl-1,3-diazaspiro[4.5]decan-2-one SC_3134 trans-4-(8-Ethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)-3-methoxy- benzonitrile SC_3135 cis-4-(8-Ethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)-3-methoxy- benzonitrile SC_3136 cis-3-[2-(4-Acetyl-piperazin-1-yl)-pyrimidin-5-yl]-8-dimethylamino-8-phenyl-1,3- diazaspiro[4.5]decan-2-one SC_3137 cis-8-Dimethylamino-8-phenyl-3-(2-pyridin-4-yl-pyrimidin-5-yl)-1,3- diazaspiro[4.5]decan-2-one SC_3138 cis-8-Dimethylamino-8-phenyl-3-(2-pyridin-3-yl-pyrimidin-5-yl)-1,3- diazaspiro[4.5]decan-2-one SC_3139 cis-5-(8-Dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)-N-(2- hydroxy-ethyl)-pyrimidine-2-carboxylic acid amide SC_3140 cis-5-(8-Dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl) pyrimidine-2-carboxylic acid amide SC_3141 cis-8-Dimethylamino-3-[2-morpholin-4-yl-4-(trifluoromethyl)-pyrimidin-5-yl]-8- phenyl-1,3-diazaspiro[4.5]decan-2-one SC_3142 cis-4-[5-(8-Dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)- pyrimidin-2-yl]-benzonitrile SC_3143 cis-5-(8-Ethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-4-methoxy- pyrimidine-2-carbonitrile SC_3144 trans-5-(8-Ethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-4-methoxy- pyrimidine-2-carbonitrile SC_3145 cis-8-Dimethylamino-3-[2-(morpholine-4-carbonyl)-pyrimidin-5-yl]-8-phenyl-1,3- diazaspiro[4.5]decan-2-one SC_3146 cis-2-[4-[5-(8-Dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)- pyrimidin-2-yl]-piperazin-1-yl]-acetic acid methyl ester SC_3147 cis-8-Dimethylamino-3-[2-(methylsulfonyl-methyl)-phenyl]-8-phenyl-1,3- diazaspiro[4.5]decan-2-one SC_3148 cis-8-Dimethylamino-3-(4-methyl-2-morpholin-4-yl-pyrimidin-5-yl)-8-phenyl-1,3- diazaspiro[4.5]decan-2-one SC_3149 cis-8-Dimethylamino-3-[2-(1,1-dioxo-[1,4]thiazinan-4-yl)-pyrimidin-5-yl]-8- phenyl-1,3-diazaspiro[4.5]decan-2-one SC_3150 cis-8-Dimethylamino-3-(4-fluoro-pyridin-3-yl)-8-phenyl-1,3-diazaspiro[4.5]decan- 2-one SC_3151 cis-5-(8-Dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)-N-(2- hydroxy-ethyl)-N-methyl-pyrimidine-2-carboxylic acid amide SC_3152 cis-5-(8-Dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)-2- morpholin-4-yl-isonicotinonitrile SC_3153 cis-4-(8-Dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-benzamide SC_3154 cis-8-Dimethylamino-3-(2-fluoro-4-methylsulfonyl-phenyl)-8-phenyl-1,3- diazaspiro[4.5]decan-2-one SC_3155 cis-4-(8-Dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)-3-fluoro- benzonitrile SC_3156 cis-4-(8-Dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)-3,5- difluoro-benzonitrile SC_3157 cis-8-Dimethylamino-3-(2-methoxy-pyrimidin-5-yl)-8-phenyl-1,3- diazaspiro[4.5]decan-2-one SC_3158 cis-3-[2-(Benzylamino)-pyrimidin-5-yl]-8-dimethylamino-8-phenyl-1,3- diazaspiro[4.5]decan-2-one SC_3159 cis-8-Dimethylamino-3-[2-(4-fluorophenyl)-pyrimidin-5-yl]-8-phenyl-1,3- diazaspiro[4.5]decan-2-one SC_3160 trans-8-Benzyl-8-dimethylamino-3-(2-morpholin-4-yl-pyrimidin-5-yl)-1,3- diazaspiro[4.5]decan-2-one SC_3161 cis-8-Benzyl-8-dimethylamino-3-(2-morpholin-4-yl-pyrimidin-5-yl)-1,3- diazaspiro[4.5]decan-2-one SC_3162 cis-8-Dimethylamino-8-phenyl-3-(2-pyridin-2-yl-pyrimidin-5-yl)-1,3- diazaspiro[4.5]decan-2-one SC_3163 cis-4-(8-Dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)-3,5- difluoro-benzamide SC_3164 cis-4-(8-Dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)-3-fluoro- benzamide SC_3165 cis-8-Benzyl-8-dimethylamino-3-[2-(trifluoromethyl)-pyrimidin-5-yl]-1,3- diazaspiro[4.5]decan-2-one SC_3166 trans-8-Benzyl-8-dimethylamino-3-[2-(trifluoromethyl)-pyrimidin-5-yl]-1,3- diazaspiro[4.5]decan-2-one SC_3167 cis-8-Dimethylamino-8-thiophen-2-yl-3-[2-(trifluoromethyl)-pyrimidin-5-yl]-1,3- diazaspiro[4.5]decan-2-one SC_3168 trans-8-Dimethylamino-8-thiophen-2-yl-3-[2-(trifluoromethyl)-pyrimidin-5-yl]- 1,3-diazaspiro[4.5]decan-2-one SC_3169 cis-2-[2-(8-Dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl) phenoxy]-acetic acid SC_3170 cis-8-Dimethylamino-8-phenyl-3-(2-piperidin-1-yl-pyrimidin-5-yl)-1,3- diazaspiro[4.5]decan-2-one SC_3171 cis-8-Dimethylamino-8-phenyl-3-(2-pyrrolidin-1-yl-pyrimidin-5-yl)-1,3- diazaspiro[4.5]decan-2-one SC_3172 cis-8-Dimethylamino-8-phenyl-3-(2-pyrimidin-5-yl-pyrimidin-5-yl)-1,3- diazaspiro[4.5]decan-2-one SC_3173 cis-8-Dimethylamino-8-phenyl-3-[2-(piperazine-1-carbonyl)-pyrimidin-5-yl]-1,3- diazaspiro[4.5]decan-2-one SC_3174 trans-8-Benzyl-8-dimethylamino-3-[4-methyl-6-(trifluoromethyl)-pyridin-3-yl]- 1,3-diazaspiro[4.5]decan-2-one SC_3175 cis-5-(8-Dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)-2- morpholin-4-yl-pyridine-4-carboxylic acid amide SC_3176 cis-8-Dimethylamino-3-[2-(3,5-dimethyl-isoxazol-4-yl)-pyrimidin-5-yl]-8-phenyl- 1,3-diazaspiro[4.5]decan-2-one SC_3177 cis-3-[2-(Benzothiazol-6-yl)-pyrimidin-5-yl]-8-dimethylamino-8-phenyl-1,3- diazaspiro[4.5]decan-2-one SC_3178 cis-8-Dimethylamino-3-[2-fluoro-4-(trifluoromethyl)-phenyl]-8-phenyl-1,3- diazaspiro[4.5]decan-2-one SC_3179 cis-8-Dimethylamino-3-(6-morpholin-4-yl-pyridin-3-yl)-8-phenyl-1,3- diazaspiro[4.5]decan-2-one SC_3180 cis-8-Dimethylamino-8-phenyl-3-(2-phenyl-thiazol-4-yl)-1,3-diazaspiro[4.5[decan- 2-one SC_3181 cis-8-Dimethylamino-8-phenyl-3-[2-(tetrahydro-pyran-4-ylamino)-pyrimidin-5-yl]- 1,3-diazaspiro[4.5]decan-2-one SC_3182 cis-8-Dimethylamino-3-[2-(4-hydroxy-piperidin-1-yl)-pyrimidin-5-yl]-8-phenyl- 1,3-diazaspiro[4.5]decan-2-one SC_3183 cis-8-Dimethylamino-8-phenyl-3-(4-phenyl-thiazol-2-yl)-1,3-diazaspiro[4.5]decan- 2-one SC_3184 cis-8-Dimethylamino-8-phenyl-3-[2-(1H-pyrrolo[2,3-b]pyridin-1-yl)-pyrimidin-5- yl]-1,3-diazaspiro[4.5]decan-2-one SC_3185 cis-8-Dimethylamino-8-phenyl-3-[2-(3,4,5-trifluoro-phenyl)-pyrimidin-5-yl]-1,3- diazaspiro[4.5]decan-2-one SC_3186 cis-8-Dimethylamino-3-o-tolyl-8-phenyl-1,3-diazaspiro[4.5]decan-2-one SC_3187 cis-8-Dimethylamino-3-m-tolyl-8-phenyl-1,3-diazaspiro[4.5]decan-2-one SC_3188 cis-8-Dimethylamino-8-phenyl-3-p-tolyl-1,3-diazaspiro[4.5]decan-2-one SC_3189 cis-8-Dimethylamino-8-phenyl-3-[4-(trifluoromethyl)-phenyl]-1,3- diazaspiro[4.5]decan-2-one SC_3190 cis-8-Dimethylamino-8-phenyl-3-[3-(trifluoromethyloxy)-phenyl]-1,3- diazaspiro[4.5]decan-2-one SC_3191 cis-8-Dimethylamino-8-phenyl-3-[4-(trifluoromethyloxy)-phenyl]-1,3- diazaspiro[4.5]decan-2-one SC_3192 cis-2-(8-Dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)-benzoic acid methyl ester SC_3193 cis-3-(8-Dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)-benzoic acid methyl ester SC_3194 cis-4-(8-Dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)-benzoic acid methyl ester SC_3195 cis-3-(1,3-Benzodioxol-5-yl)-8-dimethylamino-8-phenyl-1,3-diazaspiro[4.5]decan- 2-one SC_3196 cis-8-Dimethylamino-8-phenyl-3-quinolin-5-yl-1,3-diazaspiro[4.5]decan-2-one SC_3197 cis-3-(2,3-Dihydro-1H-indol-6-yl)-8-dimethylamino-8-phenyl-1,3- diazaspiro[4.5]decan-2-one SC_3198 cis-5-(8-Dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)-4-methyl- pyridine-2-carboxylic acid methyl ester SC_3199 cis-8-Dimethylamino-3-(6-methoxy-4-methyl-pyridin-3-yl)-8-phenyl-1,3- diazaspiro[4.5]decan-2-one SC_3200 cis-8-Dimethylamino-3-[2-methyl-5-(trifluoromethyl)-2H-pyrazol-3-yl]-8-phenyl- 1,3-diazaspiro[4.5]decan-2-one SC_3201 cis-8-Dimethylamino-3-(3-methoxy-pyridin-2-yl)-8-phenyl-1,3- diazaspiro[4.5]decan-2-one SC_3202 cis-8-Dimethylamino-8-phenyl-3-[5-(trifluoromethyl)-pyridin-2-yl]-1,3- diazaspiro[4.5]decan-2-one SC_3203 cis-5-(8-Dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)- nicotinonitrile SC_3204 cis-8-Dimethylamino-3-(3-methyl-pyridin-2-yl)-8-phenyl-1,3- diazaspiro[4.5]decan-2-one SC_3205 cis-8-Dimethylamino-3-(6-methoxy-pyridin-3-yl)-8-phenyl-1,3- diazaspiro[4.5]decan-2-one SC_3206 cis-8-Dimethylamino-8-phenyl-3-[3-(trifluoromethyl)phenyl]-1,3- diazaspiro[4.5]decan-2-one SC_3207 cis-3-(1,3-Benzodioxol-4-yl)-8-dimethylamino-8-phenyl-1,3-diazaspiro[4.5]decan- 2-one SC_3208 cis-8-Dimethylamino-3-[2-(2-oxo-1,3-dihydro-indol-4-yl)-pyrimidin-5-yl]-8- phenyl-1,3-diazaspiro[4.5]decan-2-one SC_3209 cis-8-Dimethylamino-3-[2-(3,5-dimethyl-1H-pyrazol-1-yl)-pyrimidin-5-yl]-8- phenyl-1,3-diazaspiro[4.5]decan-2-one SC_3210 cis-8-Dimethylamino-3-[2-(3-hydroxy-piperidin-1-yl)-pyrimidin-5-yl]-8-phenyl- 1,3-diazaspiro[4.5]decan-2-one SC_3211 cis-8-Dimethylamino-3-[2-(3-hydroxy-piperidin-1-yl)-pyrimidin-5-yl]-8-phenyl- 1,3-diazaspiro[4.5]decan-2-one SC_3212 cis-8-Dimethylamino-3-[2-[4-(2-hydroxy-ethyl)-piperazin-1-yl]-pyrimidin-5-yl]-8- phenyl-1,3-diazaspiro[4.5]decan-2-one SC_3213 cis-2-[4-[5-(8-Dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)- pyrimidin-2-yl]-piperazin-1-yl]-acetic acid SC_3214 cis-8-Dimethylamino-3-[2-(1-methyl-1H-pyrrolo[2,3-b]pyridin-4-yl)-pyrimidin-5- yl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one SC_3215 cis-8-Benzyl-8-dimethylamino-3-[4-methyl-6-(trifluoromethyl)-pyridin-3-yl]-1,3- diazaspiro[4.5]decan-2-one SC_3216 trans-8-Dimethylamino-3-[4-methyl-6-(trifluoromethyl)-pyridin-3-yl]-8-thiophen- 2-yl-1,3-diazaspiro[4.5]decan-2-one SC_3217 cis-8-Dimethylamino-3-[4-methyl-6-(trifluoromethyl)-pyridin-3-yl]-8-thiophen-2- yl-1,3-diazaspiro[4.5]decan-2-one SC_3218 cis-8-Dimethylamino-3-[2-(1,1-dioxo-[1,4]thiazinan-4-yl)-4-(trifluoromethyl)- pyrimidin-5-yl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one SC_3219 cis-8-Dimethylamino-8-(1-methyl-1H-benzoimidazol-2-yl)-3-[2-(trifluoromethyl)- pyrimidin-5-yl]-1,3-diazaspiro[4.5]decan-2-one SC_3220 cis-8-Dimethylamino-8-(1-methyl-1H-benzoimidazol-2-yl)-3-[4-methyl-6- (trifluoromethyl)-pyridin-3-yl]-1,3-diazaspiro[4.5]decan-2-one SC_3221 cis-8-Dimethylamino-3-[2-(2-hydroxy-ethylamino)-pyrimidin-5-yl]-8-phenyl-1,3- diazaspiro[4.5]decan-2-one SC_3222 cis-3-[2-(Benzyl-methyl-amino)-pyrimidin-5-yl]-8-dimethylamino-8-phenyl-1,3- diazaspiro[4.5]decan-2-one SC_3223 cis-5-(8-Dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)-N-[2-[2- [2-(2-methoxy-ethoxy)-ethoxy]-ethoxy]-ethyl]-pyrimidine-2-carboxylic acid amide SC_3224 cis-8-Dimethylamino-3-[2-(1H-indazol-1-yl)-pyrimidin-5-yl]-8-phenyl-1,3 diazaspiro[4.5]decan-2-one SC_3225 cis-8-Dimethylamino-3-[2-[(2-hydroxy-ethyl)-methyl-amino]-pyrimidin-5-yl]-8- phenyl-1,3-diazaspiro[4.5]decan-2-one SC_3226 cis-3-(8-Dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)-benzamide SC_3227 cis-8-Dimethylamino-3-[3-fluoro-5-(trifluoromethyl)-pyridin-2-yl]-8-phenyl-1,3- diazaspiro[4.5]decan-2-one SC_3228 cis-8-Dimethylamino-3-(5-methyl-pyrazin-2-yl)-8-phenyl-1,3- diazaspiro[4.5]decan-2-one SC_3229 cis-8-Dimethylamino-3-(5-fluoro-pyrimidin-4-yl)-8-phenyl-1,3- diazaspiro[4.5]decan-2-one SC_3230 cis-8-Dimethylamino-3-(5-fluoro-pyrimidin-2-yl)-8-phenyl-1,3- diazaspiro[4.5]decan-2-one SC_3231 cis-8-Dimethylamino-8-phenyl-3-pyrazin-2-yl-1,3-diazaspiro[4.5]decan-2-one SC_3232 cis-3-([2,1,3]Benzoxadiazol-5-yl)-8-dimethylamino-8-phenyl-1,3- diazaspiro[4.5]decan-2-one SC_3233 cis-2-[2-(8-Dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)- phenoxy]-acetamide SC_3234 cis-8-Dimethylamino-8-phenyl-3-(5-pyridin-4-yl-thiophen-2-yl)-1,3- diazaspiro[4.5]decan-2-one SC_3235 cis-2-[2-(8-Dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)- phenoxy]-acetic acid methyl ester SC_3236 cis-8-Dimethylamino-3-(2-morpholin-4-yl-pyrimidin-4-yl)-8-phenyl-1,3- diazaspiro[4.5]decan-2-one SC_3237 cis-3-[2-(3,4-Difluoro-phenyl)-pyrimidin-5-yl]-8-dimethylamino-8-phenyl-1,3- diazaspiro[4.5]decan-2-one SC_3238 cis-2-[5-(8-Dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)- pyrimidin-2-yl]-benzonitrile SC_3239 cis-3-(2-Amino-pyrimidin-5-yl)-8-dimethylamino-8-phenyl-1,3- diazaspiro[4.5]decan-2-one SC_3240 cis-N-[5-(8-Dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)- pyrimidin-2-yl]-cyclopropanecarboxylic acid amide SC_3241 cis-2-[4-[5-(8-Dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)- pyrimidin-2-yl]-piperazin-1-yl]-acetamide SC_3242 cis-8-Dimethylamino-8-phenyl-3-(6-piperazin-1-yl-pyridin-3-yl)-1,3- diazaspiro[4.5]decan-2-one SC_3243 cis-8-Dimethylamino-3-[6-(4-methyl-piperazin-1-yl)-pyridin-3-yl]-8-phenyl-1,3- diazaspiro[4.5]decan-2-one SC_3244 cis-8-Dimethylamino-3-[2-(1,1-dioxo-[1,4]thiazinan-4-yl)-4-methyl-pyrimidin-5- yl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one SC_3245 cis-8-Dimethylamino-8-phenyl-3-[2-(trifluoromethyl)-pyrimidin-5-yl]-1,3- diazaspiro[4.5]decan-2-one SC_3246 cis-2-[8-Dimethylamino-1-(3-methoxy-propyl)-2-oxo-8-phenyl-1,3- diazaspiro[4.5]decan-3-yl]-pyrimidine-5-carbonitrile SC_3247 cis-8-Dimethylamino-3-[2-(4-methyl-piperazin-1-yl)-pyrimidin-5-yl]-8-phenyl-1,3- diazaspiro[4.5]decan-2-one SC_3248 cis-8-Dimethylamino-1-[(1-hydroxy-cyclobutyl)-methyl]-8-phenyl-3-[2- (trifluoromethyl)-pyrimidin-5-yl]-1,3-diazaspiro[4.5]decan-2-one SC_3249 cis-2-[1-(3-Methoxy-propyl)-8-methylamino-2-oxo-8-phenyl-1,3- diazaspiro[4.5]decan-3-yl]-pyrimidine-5-carbonitrile SC_3250 cis-8-Dimethylamino-8-phenyl-3-[6-(trifluoromethyl)-pyridin-3-yl]-1,3- diazaspiro[4.5]decan-2-one SC_3251 cis-5-(8-Dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)-pyridine- 2-carbonitrile SC_3252 cis-8-Dimethylamino-3-(2-morpholin-4-yl-pyrimidin-5-yl)-8-phenyl-1,3- diazaspiro[4.5]decan-2-one SC_3253 cis-8-Dimethylamino-3-(2-methyl-pyrimidin-5-yl)-8-phenyl-1,3- diazaspiro[4.5]decan-2-one SC_3254 cis-8-Dimethylamino-1-[(2-methoxyphenyl)-methyl]-3-(2-methyl-pyrimidin-5-yl)- 8-phenyl-1,3-diazaspiro[4.5]decan-2-one SC_3255 cis-1-[(1-Hydroxy-cyclobutyl)-methyl]-8-methylamino-8-phenyl-3-[2- (trifluoromethyl)-pyrimidin-5-yl]-1,3-diazaspiro[4.5]decan-2-one SC_3256 cis-8-Dimethylamino-1-[(1-hydroxy-cyclobutyl)-methyl]-3-(2-methyl-pyrimidin-5- yl)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one SC_3257 cis-1-[(1-Hydroxy-cyclobutyl)-methyl]-8-methylamino-8-phenyl-3-pyrimidin-5-yl 1,3-diazaspiro[4.5]decan-2-one SC_3258 cis-5-(8-Dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)-4-methyl- pyridine-2-carbonitrile SC_3259 cis-8-Dimethylamino-3-(2-methyl-pyrimidin-5-yl)-8-phenyl-1-(pyridin-2-yl- methyl)-1,3-diazaspiro[4.5]decan-2-one SC_3260 cis-8-Dimethylamino-8-phenyl-3-pyrimidin-5-yl-1,3-diazaspiro[4.5]decan-2-one SC_3261 cis-8-Dimethylamino-1-[(1-hydroxy-cyclobutyl)-methyl]-8-phenyl-3-pyrimidin-5- yl-1,3-diazaspiro[4.5]decan-2-one SC_3262 cis-8-Amino-1-[(1-hydroxy-cyclobutyl)-methyl]-8-phenyl-3-[2-(trifluoromethyl)- pyrimidin-5-yl]-1,3-diazaspiro[4.5]decan-2-one SC_3263 cis-8-Dimethylamino-3-(3-fluorophenyl)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one SC_3264 cis-8-Dimethylamino-3-(3-methylsulfonyl-phenyl)-8-phenyl-1,3- diazaspiro[4.5]decan-2-one SC_3265 cis-8-Dimethylamino-3-(4-methylsulfonyl-phenyl)-8-phenyl-1,3- diazaspiro[4.5]decan-2-one SC_3266 cis-8-Dimethylamino-8-phenyl-3-pyridazin-3-yl-1,3-diazaspiro[4.5]decan-2-one SC_3267 cis-3-Methoxy-4-(8-methylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)- benzonitrile SC_3268 cis-8-Dimethylamino-3-(2-fluorophenyl)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one SC_3269 cis-8-Dimethylamino-8-phenyl-3-(2-phenyl-pyrimidin-5-yl)-1,3- diazaspiro[4.5]decan-2-one SC_3270 cis-8-Methylamino-1-(oxetan-3-yl-methyl)-8-phenyl-3-[2-(trifluoromethyl)- pyrimidin-5-yl]-1,3-diazaspiro[4.5]decan-2-one SC_3271 cis-1-(Cyclopropyl-methyl)-8-methylamino-8-phenyl-3-[2-(trifluoromethyl)- pyrimidin-5-yl]-1,3-diazaspiro[4.5]decan-2-one SC_3272 cis-4-(8-Dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)- benzonitrile SC_3273 cis-8-Dimethylamino-3-(4-fluorophenyl)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one SC_3274 cis-2-(8-Dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)- benzonitrile SC_3275 cis-8-Ethylamino-1-[(1-hydroxy-cyclobutyl)-methyl]-8-phenyl-3-[2- (trifluoromethyl)-pyrimidin-5-yl]-1,3-diazaspiro[4.5]decan-2-one SC_3276 cis-1-[(1-Hydroxy-cyclobutyl)-methyl]-8-methylamino-3-(2-methyl-pyrimidin-5- yl)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one SC_3277 cis-8-Dimethylamino-3-[2-(morpholin-4-yl-methyl)-pyrimidin-5-yl]-8-phenyl-1,3- diazaspiro[4.5]decan-2-one SC_3278 cis-8-Dimethylamino-3-[2-(methyl-tetrahydro-pyran-4-yl-amino)-pyrimidin-5-yl]- 8-phenyl-1,3-diazaspiro[4.5]decan-2-one SC_3279 cis-5-[8-Dimethylamino-1-[(1-hydroxy-cyclobutyl)-methyl]-2-oxo-8-phenyl-1,3- diazaspiro[4.5]decan-3-yl]-N-[2-[2-[2-(2-methoxy-ethoxy)-ethoxyl-ethoxy]-ethyl]- pyrimidine-2-carboxylic acid amide SC_3280 cis-1-(Cyclopropyl-methyl)-3-(2-fluoro-4-methylsulfonyl-phenyl)-8-methylamino- 8-phenyl-1,3-diazaspiro[4.5]decan-2-one SC_3281 cis-2-[[5-(8-Dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)- pyrimidin-2-yl]-methyl-aminol-acetamide SC_3282 cis-2-[[5-(8-Dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)- pyrimidin-2-yl]amino]-acetamide SC_3283 cis-1-(Cyclopropyl-methyl)-8-methylamino-3-[4-methyl-6-(trifluoromethyl)- pyridin-3-yl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one SC_3284 cis-1-(Cyclopropyl-methyl)-8-dimethylamino-3-[4-methyl-6-(trifluoromethyl)- pyridin-3-yl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one SC_3285 cis-N-[5-(8-Dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)- pyrimidin-2-yl]-thiophene-2-carboxylic acid amide SC_3286 cis-N-[5-(8-Dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)- pyrimidin-2-yl]-benzamide SC_3287 cis-8-Dimethylamino-8-phenyl-3-(5-phenyl-thiophen-2-yl)-1,3- diazaspiro[4.5]decan-2-one SC_3288 cis-1-(Cyclopropyl-methyl)-8-methylamino-3-[2-(methylsulfonyl-methyl)- phenyl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one SC_3289 cis-1-(Cyclopropyl-methyl)-8-dimethylamino-3-[2-(methylsulfonyl-methyl)-phenyl]- 8-phenyl-1,3-diazaspiro[4.5]decan-2-one SC_3290 cis-8-Dimethylamino-8-(3-fluorophenyl)-3-[2-(methylsulfonyl-methyl)-phenyl]- 1,3-diazaspiro[4.5]decan-2-one SC_3291 cis-8-Dimethylamino-8-(4-fluorophenyl)-3-[2-(methylsulfonyl-methyl)-phenyl]- 1,3-diazaspiro[4.5]decan-2-one SC_3292 cis-8-[Methyl-(tetrahydro-furan-3-yl-methyl)-amino]-8-phenyl-3-[2- (trifluoromethyl)-pyrimidin-5-yl]-1,3-diazaspiro[4.5]decan-2-one (enantiomer 1) SC_3293 cis-8-[Methyl-(tetrahydro-furan-3-yl-methyl)-amino]-8-phenyl-3-[2- (trifluoromethyl)-pyrimidin-5-yl]-1,3-diazaspiro[4.5]decan-2-one (enantiomer 2) SC_3294 cis-8-Dimethylamino-8-(3-fluorophenyl)-3-(4-methyl-2-morpholin-4-yl-pyrimidin- 5-yl)-1,3-diazaspiro[4.5]decan-2-one SC_3295 cis-3-[6-(4-Acetyl-piperazin-1-yl)-4-methyl-pyridin-3-yl]-8-dimethylamino-8- phenyl-1,3-diazaspiro[4.5]decan-2-one SC_3296 cis-3-[2-(4-Acetyl-piperazin-1-yl)-4-methyl-pyrimidin-5-yl]-8-dimethylamino-8- phenyl-1,3-diazaspiro[4.5]decan-2-one SC_3297 cis-8-Dimethylamino-3-(4-methyl-6-pyridin-4-yl-pyridin-3-yl)-8-phenyl-1,3- diazaspiro[4.5]decan-2-one SC_3298 cis-3-[2-(4-Acetyl-piperazin-1-yl)-4-(trifluoromethyl)-pyrimidin-5-yl]-8- dimethylamino-8-phenyl-1,3-diazaspiro[4.5]decan-2-one SC_3299 cis-8-Dimethylamino-3-[2-(3-oxo-piperazin-1-yl)-4-(trifluoromethyl)-pyrimidin-5- yl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one SC_3300 cis-8-Dimethylamino-3-isoquinolin-4-yl-8-phenyl-1,3-diazaspiro[4.5]decan-2-one SC_3301 cis-8-Dimethylamino-3-isoquinolin-5-yl-8-phenyl-1,3-diazaspiro[4.5]decan-2-one SC_3302 cis-8-Dimethylamino-8-phenyl-3-(1H-pyrrolo[2,3-b]pyridin-4-yl)-1,3- diazaspiro[4.5]decan-2-one SC_3303 cis-8-Dimethylamino-8-phenyl-3-(2-pyridin-4-yl-thiazol-4-yl)-1,3- diazaspiro[4.5]decan-2-one SC_3304 cis-8-[Methyl-(tetrahydro-furan-3-yl-methyl)-amino]-3-(2-morpholin-4-yl- pyrimidin-5-yl)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one (enantiomer 1) SC_3305 cis-8-[Methyl-(tetrahydro-furan-3-yl-methyl)-amino]-3-(2-morpholin-4-yl- pyrimidin-5-yl)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one (enantiomer 2) SC_3306 cis-3-[2-(Azetidin-1-yl)-pyrimidin-5-yl]-8-dimethylamino-8-phenyl-1,3- diazaspiro[4.5]decan-2-one SC_3307 cis-3-[2-(3,3-Difluoro-azetidin-1-yl)-pyrimidin-5-yl]-8-dimethylamino-8-phenyl- 1,3-diazaspiro[4.5]decan-2-one SC_3308 cis-8-Dimethylamino-3-[6-morpholin-4-yl-5-(trifluoromethyl)-pyridin-3-yl]-8- phenyl-1,3-diazaspiro[4.5]decan-2-one SC_3309 cis-8-Methylamino-3-[6-morpholin-4-yl-5-(trifluoromethyl)-pyridin-3-yl]-8- phenyl-1,3-diazaspiro[4.5]decan-2-one SC_3310 cis-8-Dimethylamino-8-phenyl-3-[5-(trifluoromethyloxy)-pyridin-2-yl]-1,3- diazaspiro[4.5]decan-2-one SC_3311 cis-8-Dimethylamino-3-(5-methylsulfonyl-pyridin-2-yl)-8-phenyl-1,3- diazaspiro[4.5]decan-2-one SC_3312 cis-6-(8-Dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)- nicotinonitrile SC_3313 cis-3-[2-(4-Cyclopropyl-1H-[1,2,3]triazol-1-yl)-pyrimidin-5-yl]-8-dimethylamino- 8-phenyl-1,3-diazaspiro[4.5]decan-2-one SC_3314 cis-8-Dimethylamino-3-[4-methyl-2-(3-oxo-piperazin-1-yl)-pyrimidin-5-yl]-8- phenyl-1,3-diazaspiro[4.5]decan-2-one SC_3315 cis-5-(8-Dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)-pyridine- 2-carboxylic acid amide SC_3316 cis-3-[4-(Azetidin-1-yl)-2-methyl-pyrimidin-5-yl]-8-dimethylamino-8-phenyl-1,3- diazaspiro[4.5]decan-2-one SC_3317 cis-2-(8-Dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)-benzamide SC_3318 cis-8-Dimethylamino-3-[2-(methylsulfonyl-methyl)-phenyl]-8-thiophen-2-yl-1,3- diazaspiro[4.5]decan-2-one SC_3319 cis-8-Dimethylamino-8-(3-fluorophenyl)-3-[2-methyl-5-(trifluoromethyl)-2H- pyrazol-3-yl]-1,3-diazaspiro[4.5]decan-2-one SC_3320 cis-8-Dimethylamino-3-(4-methyl-2-morpholin-4-yl-pyrimidin-5-yl)-8-thiophen-2- yl-1,3-diazaspiro[4.5]decan-2-one SC_3321 cis-8-Dimethylamino-3-(6-methylsulfonyl-pyridin-3-yl)-8-phenyl-1,3- diazaspiro[4.5]decan-2-one SC_3322 cis-8-Dimethylamino-8-phenyl-3-(1H-pyrrolo[2,3-b]pyridin-5-yl)-1,3- diazaspiro[4.5]decan-2-one SC_3323 cis-N-[5-(8-Dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)- pyrimidin-2-yl]-acetamide SC_3324 cis-3-[2-(4-Methyl-piperazin-1-yl)-pyrimidin-5-yl]-8-[methyl-(tetrahydro-furan-3- yl-methyl)-amino]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one (enantiomer 1) SC_3325 cis-3-[2-(4-Methyl-piperazin-1-yl)-pyrimidin-5-yl]-8-[methyl-(tetrahydro-furan-3- yl-methyl)-amino]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one (enantiomer 2) SC_3326 cis-8-Dimethylamino-3-(4,6-dimethyl-2-morpholin-4-yl-pyrimidin-5-yl)-8-phenyl- 1,3-diazaspiro[4.5]decan-2-one SC_3327 cis-8-Dimethylamino-3-(2-morpholin-4-yl-pyrimidin-5-yl)-8-thiophen-2-yl-1,3- diazaspiro[4.5]decan-2-one SC_3328 cis-6-(8-Dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)-pyridine- 3-carboxylic acid amide SC_3329 cis-8-Dimethylamino-3-[2-methyl-5-(trifluoromethyl)-2H-pyrazol-3-yl]-8- thiophen-2-yl-1,3-diazaspiro[4.5]decan-2-one SC_3330 cis-8-Dimethylamino-3-[2-[(2-hydroxy-ethyl)-methyl-amino]-pyrimidin-5-yl]-8- thiophen-2-yl-1,3-diazaspiro[4.5]decan-2-one SC_3331 cis-8-Dimethylamino-3-[2-(2-oxo-1,3-dihydro-indol-4-yl)-pyrimidin-5-yl]-8- thiophen-2-yl-1,3-diazaspiro[4.5]decan-2-one SC_3332 cis-8-Dimethylamino-3-[4-methyl-6-(3-oxo-piperazin-1-yl)-pyridin-3-yl]-8-phenyl- 1,3-diazaspiro[4.5]decan-2-one SC_3333 cis-8-Dimethylamino-3-(4-methyl-6-pyridin-2-yl-pyridin-3-yl)-8-phenyl-1,3- diazaspiro[4.5]decan-2-one SC_3334 cis-8-Dimethylamino-3-(4-methylsulfonyl-pyridin-3-yl)-8-phenyl-1,3- diazaspiro[4.5]decan-2-one SC_3335 cis-3-(Benzothiazol-7-yl)-8-dimethylamino-8-phenyl-1,3-diazaspiro[4.5]decan-2-one SC_3336 cis-8-Dimethylamino-8-(4-fluorophenyl)-3-(4-methyl-2-morpholin-4-yl-pyrimidin- 5-yl)-1,3-diazaspiro[4.5]decan-2-one SC_3337 cis-2-[8-Dimethylamino-3-[4-methyl-6-(trifluoromethyl)-pyridin-3-yl]-2-oxo-8- phenyl-1,3-diazaspiro[4.5]decan-1-yl]-N,N-dimethyl-acetamide SC_3338 cis-8-Dimethylamino-3-[2-(2-methyl-1-oxo-2,3-dihydro-isoindol-4-yl)-pyrimidin- 5-yl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one SC_3339 cis-2-[[5-(8-Dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)-2- methyl-pyrimidin-4-yl]amino]-acetamide SC_3340 cis-2-[3-(8-Dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)-pyridin- 4-yl]-acetamide SC_3341 cis-8-Dimethylamino-3-[4-(methylsulfonyl-methyl)-pyridin-3-yl]-8-phenyl-1,3- diazaspiro[4.5]decan-2-one SC_3342 cis-8-Dimethylamino-3-[6-(4-methyl-3-oxo-piperazin-1-yl)-pyridin-3-yl]-8-phenyl- 1,3-diazaspiro[4.5]decan-2-one SC_3343 cis-8-Dimethylamino-3-(2,4-dimethyl-pyrimidin-5-yl)-8-phenyl-1,3- diazaspiro[4.5]decan-2-one SC_3344 cis-8-Dimethylamino-3-[2-(1-oxo-2,3-dihydro-isoindol-4-yl)-pyrimidin-5-yl]-8- phenyl-1,3-diazaspiro[4.5]decan-2-one; 2,2,2-trifluoro-acetic acid SC_3345 cis-8-Dimethylamino-3-[6-[(2-hydroxy-ethyl)-methyl-amino]-5-(trifluoromethyl)- pyridin-3-yl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one SC_3346 cis-8-Dimethylamino-8-phenyl-3-[2-[4-(trifluoromethyl)-1H-[1,2,3]triazol-1-yl]- pyrimidin-5-yl]-1,3-diazaspiro[4.5]decan-2-one SC_3347 cis-8-Dimethylamino-3-[2-(4-isopropyl-1H-[1,2,3]triazol-1-yl)-pyrimidin-5-yl]-8- phenyl-1,3-diazaspiro[4.5]decan-2-one SC_3348 cis-8-Dimethylamino-3-[6-(1,1-dioxo-[1,4]thiazinan-4-yl)-pyridin-3-yl]-8-phenyl- 1,3-diazaspiro[4.5]decan-2-one SC_3349 cis-5-(8-Dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)-2- morpholin-4-yl-nicotinonitrile SC_3350 cis-8-Dimethylamino-3-(1-methylsulfonyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-8- phenyl-1,3-diazaspiro[4.5]decan-2-one SC_3351 cis-8-Dimethylamino-3-(1H-indol-4-yl)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one SC_3352 cis-8-Dimethylamino-3-(2-hydroxy-benzooxazol-7-yl)-8-phenyl-1,3 diazaspiro[4.5]decan-2-one SC_3353 cis-8-Dimethylamino-3-[2-fluoro-4-(trifluoromethyloxy)-phenyl]-8-phenyl-1,3- diazaspiro[4.5]decan-2-one SC_3354 cis-4-[5-(8-Dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)- pyrimidin-2-yl]-benzamide; 2,2,2-trifluoro-acetic acid SC_3355 cis-8-Dimethylamino-3-(1-methyl-1H-pyrrolo[2,3-b]pyridin-4-yl)-8-phenyl-1,3- diazaspiro[4.5]decan-2-one SC_3356 cis-3-(1-Acetyl-1H-indol-4-yl)-8-dimethylamino-8-phenyl-1,3- diazaspiro[4.5]decan-2-one SC_3357 cis-8-Dimethylamino-3-(1H-indol-3-yl)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one SC_3358 cis-6-(8-Dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)-5-methyl nicotinonitrile SC_3359 cis-6-(8-Dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)-5-fluoro nicotinonitrile SC_3360 cis-8-Dimethylamino-3-[4-methyl-6-(trifluoromethyl)-pyridin-3-yl]-1-(2-oxo-2- pyrrolidin-1-yl-ethyl)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one SC_3361 cis-6-(8-Dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)-5-methyl pyridine-3-carboxylic acid amide SC_3362 cis-6-(8-Dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)-5-fluoro- pyridine-3-carboxylic acid amide SC_3363 cis-8-Dimethylamino-3-[4-methyl-6-(trifluoromethyl)-pyridin-3-yl]-8-m-tolyl-1,3- diazaspiro[4.5]decan-2-one SC_3364 cis-3-(8-Dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)- isonicotinonitrile SC_3365 cis-8-Dimethylamino-3-[3-fluoro-5-(2-oxo-1,3-dihydro-indol-4-yl)-pyridin-2-yl]-8- phenyl-1,3-diazaspiro[4.5]decan-2-one SC_3366 cis-8-Dimethylamino-3-[4-methyl-6-(trifluoromethyl)-pyridin-3-yl]-8-[3 - (trifluoromethyloxy)-phenyl]-1,3-diazaspiro[4.5]decan-2-one SC_3367 cis-8-Dimethylamino-3-[4-methyl-6-(trifluoromethyl)-pyridin-3-yl]-8-[3- (trifluoromethyl)phenyl]-1,3-diazaspiro[4.5]decan-2-one SC_3368 cis-8-Dimethylamino-8-(3-methoxyphenyl)-3-[4-methyl-6-(trifluoromethyl)- pyridin-3-yl]-1,3-diazaspiro[4.5]decan-2-one SC_3369 cis-8-(5-Chloro-thiophen-2-yl)-8-dimethylamino-3-[4-methyl-6-(trifluoromethyl)- pyridin-3-yl]-1,3-diazaspiro[4.5]decan-2-one SC_3370 cis-8-Dimethylamino-8-(3-fluorophenyl)-3-[4-methyl-6-(trifluoromethyl)-pyridin- 3-yl]-1,3-diazaspiro[4.5]decan-2-one SC_3371 cis-8-Dimethylamino-3-(2-methylamino-pyrimidin-5-yl)-8-phenyl-1,3- diazaspiro[4.5]decan-2-one SC_3372 cis-8-(5-Chloro-thiophen-2-yl)-8-dimethylamino-3-(4-methyl-2-morpholin-4-yl- pyrimidin-5-yl)-1,3-diazaspiro[4.5]decan-2-one SC_3373 cis-N-[5-(8-Dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)- pyrimidin-2-yl]-N-methyl-cyclopropanecarboxylic acid amide SC_3374 cis-N-[5-(8-Dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)- pyrimidin-2-yl]-N,2,5-trimethyl-2H-pyrazole-3-carboxylic acid amide SC_3375 cis-3-[4,6-Bis(trifluoromethyl)-pyridin-3-yl]-8-dimethylamino-8-phenyl-1,3- diazaspiro[4.5]decan-2-one SC_3376 cis-8-Dimethylamino-3-[2-[(2-hydroxy-ethyl)-methyl-amino]-quinazolin-6-yl]-8- phenyl-1,3-diazaspiro[4.5]decan-2-one SC_3377 cis-8-Dimethylamino-3-(2-morpholin-4-yl-quinazolin-6-yl)-8-phenyl-1,3- diazaspiro[4.5]decan-2-one SC_3378 cis-8-[Methyl-(oxetan-3-yl-methyl)-amino]-8-phenyl-3-[2-(trifluoromethyl)- pyrimidin-5-yl]-1,3-diazaspiro[4.5]decan-2-one SC_3379 cis-3-(1-Acetyl-1H-indol-3-yl)-8-dimethylamino-8-phenyl-1,3- diazaspiro[4.5]decan-2-one SC_3380 cis-8-Dimethylamino-8-phenyl-3-quinazolin-6-yl-1,3-diazaspiro[4.5]decan-2-one SC_3381 cis-5-(8-Dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)-2-(2-oxo- 1,3-dihydro-indol-4-yl)-isonicotinonitrile SC_3382 cis-N-[5-(8-Dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)- pyrimidin-2-yl]-N-methyl-tetrahydro-pyran-4-carboxylic acid amide SC_3383 cis-N-[5-(8-Dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)- pyrimidin-2-yl]-N,2,2-trimethyl-propionamide SC_3384 cis-8-Dimethylamino-3-[2-(1-methyl-2-oxo-1,3-dihydro-indol-4-yl)-pyrimidin-5- yl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one SC_3385 cis-8-Dimethylamino-3-(2-morpholin-4-yl-1H-benzoimidazol-5-yl)-8-phenyl-1,3- diazaspiro[4.5]decan-2-one SC_3386 cis-8-Dimethylamino-8-(3-fluoro-5-methyl-phenyl)-3-[4-methyl-6- (trifluoromethyl)-pyridin-3-yl]-1,3-diazaspiro[4.5]decan-2-one SC_3387 cis-8-Dimethylamino-3-[6-(2-oxo-1,3-dihydro-indol-4-yl)-pyridin-3-yl]-8-phenyl- 1,3-diazaspiro[4.5]decan-2-one SC_3388 cis-8-Dimethylamino-8-(3-hydroxyphenyl)-3-[4-methyl-6-(trifluoromethyl)- pyridin-3-yl]-1,3-diazaspiro[4.5]decan-2-one SC_3389 cis-3-[6-(Azetidin-1-yl)-5-(trifluoromethyl)-pyridin-3-yl]-8-dimethylamino-8- phenyl-1,3-diazaspiro[4.5]decan-2-one SC_3390 cis-3-[1-(Cyclopropyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3- diazaspiro[4.5]decan-3-yl]-isonicotinonitrile SC_3391 cis-3-[3,5-Bis(trifluoromethyl)-pyridin-2-yl]-8-dimethylamino-8-phenyl-1,3- diazaspiro[4.5]decan-2-one SC_3392 cis-8-Dimethylamino-3-(5-fluoro-6-morpholin-4-yl-pyridin-3-yl)-8-phenyl-1,3- diazaspiro[4.5]decan-2-one SC_3393 cis-8-(3-Chlorophenyl)-8-dimethylamino-3-[4-methyl-6-(trifluoromethyl)-pyridin- 3-yl]-1,3-diazaspiro[4.5]decan-2-one SC_3394 cis-8-Dimethylamino-3-[5-(2-oxo-1,3-dihydro-indol-4-yl)-pyridin-2-yl]-8-phenyl- 1,3-diazaspiro[4.5]decan-2-one SC_3395 cis-8-Dimethylamino-8-phenyl-3-[5-(trifluoromethyl)-[1,3,4]thiadiazol-2-yl]-1,3- diazaspiro[4.5]decan-2-one SC_3396 cis-8-Dimethylamino-3-(2-oxo-1,3-dihydro-indol-4-yl)-8-phenyl-1,3- diazaspiro[4.5]decan-2-one SC_3397 cis-8-Dimethylamino-3-[2-[(2-hydroxy-ethyl)-methyl-amino]-1H-benzoimidazol- 5-yl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one SC_3398 cis-8-Dimethylamino-3-(5-methyl-6-morpholin-4-yl-pyridin-3-yl)-8-phenyl-1,3- diazaspiro[4.5]decan-2-one SC_3399 cis-1-(Cyclopropyl-methyl)-8-dimethylamino-8-(3-fluorophenyl)-3-(5- methylsulfonyl-pyridin-2-yl)-1,3-diazaspiro[4.5]decan-2-one SC_3400 cis-1-(Cyclopropyl-methyl)-8-(3-fluorophenyl)-8-methylamino-3-(5- methylsulfonyl-pyridin-2-yl)-1,3-diazaspiro[4.5]decan-2-one SC_3401 cis-1-(Cyclobutyl-methyl)-8-(3-fluorophenyl)-8-methylamino-3-[2- (trifluoromethyl)-pyrimidin-5-yl]-1,3-diazaspiro[4.5]decan-2-one SC_3402 cis-1-(Cyclopropyl-methyl)-8-dimethylamino-8-(3-fluorophenyl)-3-[2- (trifluoromethyl)-pyrimidin-5-yl]-1,3-diazaspiro[4.5]decan-2-one SC_3403 cis-1-(Cyclopropyl-methyl)-8-(3-fluorophenyl)-8-methylamino-3-[2- (trifluoromethyl)-pyrimidin-5-yl]-1,3-diazaspiro[4.5]decan-2-one SC_3404 cis-8-Dimethylamino-8-(3-fluorophenyl)-3-[2-(trifluoromethyl)-pyrimidin-5-yl]- 1,3-diazaspiro[4.5]decan-2-one SC_3405 cis-1-(Cyclopropyl-methyl)-8-dimethylamino-8-(3-fluorophenyl)-3-[2-methyl-5- (trifluoromethyl)-2H-pyrazol-3-yl]-1,3-diazaspiro[4.5]decan-2-one SC_3406 cis-1-(Cyclopropyl-methyl)-8-(3-fluorophenyl)-8-methylamino-3-[2-methyl-5- (trifluoromethyl)-2H-pyrazol-3-yl]1-1,3-diazaspiro[4.5]decan-2-one SC_3407 cis-8-Methylamino-3-(4-methyl-2-morpholin-4-yl-pyrimidin-5-yl)-8-phenyl-1,3- diazaspiro[4.5]decan-2-one SC_3408 cis-3-[5-(Azetidin-1-yl)-3-methyl-pyridin-2-yl]-8-dimethylamino-8-(3- fluorophenyl)-1,3-diazaspiro[4.5]decan-2-one SC_3409 cis-8-Dimethylamino-8-(3-fluorophenyl)-3-(5-methylsulfonyl-pyridin-2-yl)-1,3- diazaspiro[4.5]decan-2-one SC_3410 cis-3-(6-(azetidin-1-yl)-4-fluoropyridin-3-yl)-8-(dimethylamino)-8-phenyl-1,3- diazaspiro[4.5]decan-2-one SC_3411 cis-3-(6-(azetidin-1-yl)pyridin-3-yl)-8-(dimethylamino)-8-(3-fluorophenyl)-1,3- diazaspiro[4.5]decan-2-one SC_3412 cis-3-(1-(cyclopropanecarbonyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl)-8- (dimethylamino)-8-(3-fluorophenyl)-1,3-diazaspiro[4.5]decan-2-one SC_3413 cis-8-(dimethylamino)-8-(3-fluorophenyl)-3-(1-(2-hydroxyethyl)-3- (trifluoromethyl)-1H-pyrazol-5-yl)-1,3-diazaspiro[4.5]decan-2-one SC_3414 cis-3-(1-(cyclopropylmethyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl)-8- (dimethylamino)-8-(3-fluorophenyl)-1,3-diazaspiro[4.5]decan-2-one SC_3415 cis-8-(dimethylamino)-8-(3-fluorophenyl)-3-(1-(methylsulfonyl)-3- (trifluoromethyl)-1H-pyrazol-5-yl)-1,3-diazaspiro[4.5]decan-2-one SC_3416 cis-1-(cyclopropylmethyl)-8-(dimethylamino)-8-(3-fluorophenyl)-3-(1- (methylsulfonyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl)-1,3-diazaspiro[4.5]decan- 2-one SC_3417 cis-2-(5-(8-(dimethylamino)-8-(3-fluorophenyl)-2-oxo-1,3-diazaspiro[4.5]decan- 3-yl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)-N,N-dimethylacetamide SC_3418 cis-2-(5-(1-(cyclopropylmethyl)-8-(dimethylamino)-8-(3-fluorophenyl)-2-oxo-1,3- diazaspiro[4.5]decan-3-yl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)-N,N- dimethylacetamide SC_3419 cis-8-(dimethylamino)-3-(1-methyl1-1H-pyrrolo[2,3-b]pyridin-5-yl)-8-phenyl-1,3- diazaspiro[4.5]decan-2-one SC_3420 cis-8-(dimethylamino)-3-(3-fluoro-1H-pyrrolo[2,3-b]pyridin-5-yl)-8-phenyl-1,3- diazaspiro[4.5]decan-2-one SC_3421 cis-8-(dimethylamino)-8-phenyl-3-(1H-pyrrolo[2,3-c]pyridin-4-yl)-1,3- diazaspiro[4.5]decan-2-one SC_3422 cis-8-(dimethylamino)-8-phenyl-3-(2-(pyridazin-4-yl)pyrimidin-5-yl)-1,3- diazaspiro[4.5]decan-2-one SC_3423 cis-8-(dimethylamino)-3-(2-(2-oxo-1,2-dihydropyridin-4-yl)pyrimidin-5-yl)-8- phenyl-1,3-diazaspiro[4.5]decan-2-one SC_3424 cis-8-(dimethylamino)-8-(3-fluorophenyl)-3-(1-methyl-3-(thiophen-2-yl)-1H- pyrazol-5-yl)-1,3-diazaspiro[4.5]decan-2-one SC_3425 cis-8-(dimethylamino)-8-(3-fluorophenyl)-3-(1-methyl-3-morpholino-1H-pyrazol- 5-yl)-1,3-diazaspiro[4.5]decan-2-one SC_3426 cis-8-(dimethylamino)-8-phenyl-1-(2,2,2-trifluoroethyl)-3-(2- (trifluoromethyl)pyrimidin-5-yl)-1,3-diazaspiro[4.5]decan-2-one SC_3427 cis-8-(dimethylamino)-8-phenyl-3-(2-(trifluoromethyl)pyrimidin-5-yl)-1-(3,3,3- trifluoropropyl)-1,3-diazaspiro[4.5]decan-2-one SC_3428 cis-3-(4-methyl-6-(trifluoromethyl)pyridin-3-yl)-8-(methylamino)-8-phenyl-1,3- diazaspiro[4.5]decan-2-one SC_3429 cis-3-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)-8-(methylamino)-8-phenyl- 1,3-diazaspiro[4.5]decan-2-one SC_3430 cis-8-(dimethylamino)-8-(3-fluorophenyl)-3-(4-(methylsulfonyl)pyridin-3-yl)-1,3- diazaspiro[4.5]decan-2-one SC_3431 cis-8-(dimethylamino)-3-(1-ethyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)-8-(3- fluorophenyl)-1,3-diazaspiro[4.5]decan-2-one SC_3432 cis-3-(1-cyclopropyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)-8-(dimethylamino)-8-(3- fluorophenyl)-1,3-diazaspiro[4.5]decan-2-one SC_3433 cis-8-(dimethylamino)-8-(3-fluorophenyl)-3-(1-(oxetan-3-ylmethyl)-3- (trifluoromethyl)-1H-pyrazol-5-yl)-1,3-diazaspiro[4.5]decan-2-one SC_3434 cis-8-(dimethylamino)-8-(3-fluorophenyl)-3-(1-(2-(methylsulfonyl)ethyl)-3- (trifluoromethyl)-1H-pyrazol-5-yl)-1,3-diazaspiro[4.5]decan-2-one SC_3435 cis-8-(dimethylamino)-8-(3-fluorophenyl)-3-(4-methyl-2-(methylamino)pyrimidin- 5-yl)-1,3-diazaspiro[4.5]decan-2-one SC_3436 cis-3-(2-cyclopropoxy-4-methylpyrimidin-5-yl)-8-(dimethylamino)-8-(3- fluorophenyl)-1,3-diazaspiro[4.5]decan-2-one SC_3437 cis-N-(5-(8-(dimethylamino)-8-(3-fluorophenyl)-2-oxo-1,3-diazaspiro[4.5]decan-3- yl)-4-methylpyrimidin-2-yl)-N-methylcyclopropanecarboxamide SC_3438 cis-N-(5-(8-(dimethylamino)-8-(3-fluorophenyl)-2-oxo-1,3-diazaspiro[4.5]decan-3- yl)-4-methylpyrimidin-2-yl)-N-methylpivalamide SC_3439 cis-3-(4-(azetidin-1-yl)-2-(trifluoromethyl)pyrimidin-5-yl)-8-(dimethylamino)-8- (3-fluorophenyl)-1,3-diazaspiro[4.5]decan-2-one SC_3440 cis-8-(dimethylamino)-8-(3-fluorophenyl)-3-(4-(oxetan-3-ylmethoxy)-2- (trifluoromethyl)pyrimidin-5-yl)-1,3-diazaspiro[4.5]decan-2-one SC_3441 cis-3-(2-cyclopropyl-4-(2,2,2-trifluoroethoxy)pyrimidin-5-yl)-8-(dimethylamino)- 8-(3-fluorophenyl)-1,3-diazaspiro[4.5]decan-2-one SC_3442 cis-3-(2-cyclopropyl-4-((2-hydroxyethyl)(methyl)amino)pyrimidin-5-yl)-8- (dimethylamino)-8-(3-fluorophenyl)-1,3-diazaspiro[4.5]decan-2-one and the physiologically acceptable salts thereof.

According to the invention, unless expressly stated otherwise, “—C₁-C₄-alkyl”, “—C₁-C₆-alkyl” and any other alkyl residues can be linear or branched, saturated or unsaturated. Linear saturated alkyl includes methyl, ethyl, n-propyl, n-butyl, n-pentyl and n-hexyl. Examples of branched saturated alkyl include but are not limited to iso-propyl, sec-butyl, and tert-butyl. Examples of linear unsaturated alkyl include but are not limited to vinyl, propenyl, allyl, and propargyl.

According to the invention, unless expressly stated otherwise, “—C₁-C₄-alkyl”, “—C₁-C₆-alkyl” and any other alkyl residues can be unsubstituted, mono- or polysubstituted. Examples of substituted alkyl include but are not limited to —CH₂CH₂OH, —CH₂CH₂OCH₃, —CH₂CH₂CH₂OCH₃, —CH₂CH₂S(═O)₂CH₃, —CH₂C(═O)NH₂, —C(CH₃)₂C(═O)NH₂, —CH₂C(CH₃)₂C(═O)NH₂, and —CH₂CH₂C(═O)N(CH₃)₂.

According to the invention, unless expressly stated otherwise, “—C₁-C₆-alkylene-”, “—C₁-C₄-alkylene” and any other alkylene residue can be unsubstituted, mono- or polysubstituted. Examples of saturated alkylene include but are not limited to —CH₂—, —CH(CH₃)—, —C(CH₃)₂—, —CH₂CH₂—, —CH(CH₃)CH₂—, —CH₂CH(CH₃)—, —CH(CH₃)—CH(CH₃)—, —C(CH₃)₂CH₂—, —CH₂C(CH₃)₂—, —CH(CH₃)C(CH₃)₂—, —C(CH₃)₂CH(CH₃)—, C(CH₃)₂C(CH₃)₂—, —CH₂CH₂CH₂—, and —C(CH₃)₂CH₂CH₂—. Examples of unsaturated alkylene include but are not limited to —CH═CH—, —C≡C—, —C(CH₃)═CH—, —CH═C(CH₃)—, —C(CH₃)═C(CH₃)—, —CH₂CH═CH—, —CH═CHCH₂—, —CH═CH—CH═CH—, and —CH═CH—C≡C—.

According to the invention, unless expressly stated otherwise, “—C₁-C₆-alkylene-”, “—C₁-C₄-alkylene” and any other alkylene residue can be unsubstituted, mono- or polysubstituted. Examples of substituted —C₁-C₆-alkylene- include but are not limited to —CHF—, —CF₂—, —CHOH— and —C(═O)—.

According to the invention, moieties may be connected through —C₁-C₆-alkylene-, i.e. the moieties may not be directly bound to the core structure of compound according to general formula (I), but may be connected to the core structure of compound according to general formula (I) or its periphery through a —C₁-C₆-alkylene-linker.

According to the invention, “3-12-membered cycloalkyl moiety” means a non-aromatic, monocyclic, bicyclic or tricyclic moiety comprising 3 to 12 ring carbon atoms but no heteroatoms in the ring. Examples of preferred saturated 3-12-membered cycloalkyl moieties according to the invention include but are not limited to cyclopropane, cyclobutane, cyclopentane, cyclohexane, cycloheptane, cyclooctane, hydrindane, and decaline. Examples of preferred unsaturated 3-12-membered cycloalkyl moiety moieties according to the invention include but are not limited to cyclopropene, cyclobutene, cyclopentene, cyclopentadiene, cyclohexene, 1,3-cyclohexadiene, and 1,4-cyclohexadiene. The 3-12-membered cycloalkyl moiety, which is bonded to the compound according to the invention, in its periphery may optionally be condensed with a 3-12-membered heterocycloalkyl moiety, saturated or unsaturated, unsubstituted, mono- or polysubstituted; and/or with a 6-14-membered aryl moiety, unsubstituted, mono- or polysubstituted; and/or with a 5-14-membered heteroaryl moiety, unsubstituted, mono- or polysubstituted. Under these circumstances, the ring atoms of the condensed moieties are not included in the 3 to 12 ring atoms of the 3-12-membered cycloalkyl moiety. Examples of 3-12-membered cycloalkyl moieties condensed with 3-12-membered heterocycloalkyl moieties include but are not limited to octahydro-1H-indol, decahydroquinoline, decahydroisoquinoline, octahydro-2H-benzo[b][1,4]oxazin, and decahydro-quinoxalin, which in each case are connected through the 3-12-membered cycloalkyl moiety. Examples of 3-12-membered cycloalkyl moieties condensed with 6-14-membered aryl moieties include but are not limited to 2,3-dihydro-1H-indene and tetraline, which in each case are connected through the 3-12-membered cycloalkyl moiety. Examples of 3-12-membered cycloalkyl moieties condensed with 5-14-membered heteroaryl moieties include but are not limited to 5,6,7,8-tetrahydroquinoline and 5,6,7,8-tetrahydroquinazoline, which in each case are connected through the 3-12-membered cycloalkyl moiety.

According to the invention, the 3-12-membered cycloalkyl moiety may optionally be connected through —C₁-C₆-alkylene-, i.e. the 3-12-membered cycloalkyl moiety may not be directly bound to the compound according to general formula (I) but may be connected thereto through a —C₁-C₆-alkylene-linker. Examples include but are not limited to —CH₂-cyclopropyl, —CH₂-cyclobutyl, —CH₂-cyclopentyl, —CH₂-cyclohexyl, —CH₂CH₂-cyclopropyl, —CH₂CH₂-cyclobutyl, —CH₂CH₂-cyclopentyl, and —CH₂CH₂-cyclohexyl.

According to the invention, unless expressly stated otherwise, the 3-12-membered cycloalkyl moiety can be unsubstituted, mono- or polysubstituted. Examples of substituted 3-12-membered cycloalkyl moieties include but are not limited to —CH₂-1-hydroxy-cyclobutyl.

According to the invention, “3-12-membered heterocycloalkyl moiety” means a non-aromatic, monocyclic, bicyclic or tricyclic moiety comprising 3 to 12 ring atoms, wherein each cycle comprises independently of one another 1, 2, 3, 4 or more heteroatoms independently of one another selected from the group consisting of nitrogen, oxygen and sulfur, whereas sulfur may be oxidized (S(═O) or (S(═O)₂), whereas the remaining ring atoms are carbon atoms, and whereas bicyclic or tricyclic systems may share common heteroatom(s). Examples of preferred saturated 3-12-membered heterocycloalkyl moieties according to the invention include but are not limited to aziridin, azetidine, pyrrolidine, imidazolidine, pyrazolidine, piperidine, piperazine, triazolidine, tetrazolidine, oxiran, oxetane, tetrahydrofurane, tetrahydropyrane, thiirane, thietane, tetrahydrothiophene, diazepane, oxazolidine, isoxazolidine, thiazolidine, isothiazolidine, thiadiazolidine, morpholine, thiomorpholine. Examples of preferred unsaturated 3-12-membered heterocycloalkyl moiety moieties according to the invention include but are not limited to oxazoline, pyrazoline, imidazoline, isoxazoline, thiazoline, isothiazoline, and dihydropyran. The 3-12-membered heterocycloalkyl moiety, which is bonded to the compound according to the invention, in its periphery may optionally be condensed with a 3-12-membered cycloalkyl moiety, saturated or unsaturated, unsubstituted, mono- or polysubstituted; and/or with a 6-14-membered aryl moiety, unsubstituted, mono- or polysubstituted; and/or with a 5-14-membered heteroaryl moiety, unsubstituted, mono- or polysubstituted. Under these circumstances, the ring atoms of the condensed moieties are not included in the 3 to 12 ring atoms of the 3-12-membered heterocycloalkyl moieties. Examples of 3-12-membered heterocycloalkyl moieties condensed with 3-12-membered cycloalkyl moieties include but are not limited to octahydro-1H-indol, decahydroquinoline, decahydroisoquinoline, octahydro-2H-benzo[b][1,4]oxazin, and decahydro-quinoxalin, which in each case are connected through the 3-12-membered heterocycloalkyl moiety. An examples of a 3-12-membered heterocycloalkyl moiety condensed with a 6-14-membered aryl moiety includes but is not limited to 1,2,3,4-tetrahydroquinoline, which is connected through the 3-12-membered heterocycloalkyl moiety. An example of a 3-12-membered heterocycloalkyl moiety condensed with a 5-14-membered heteroaryl moieties includes but is not limited to 5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyrazine, which is connected through the 3-12-membered heterocycloalkyl moiety.

According to the invention, the 3-12-membered heterocycloalkyl moiety may optionally be connected through —C₁-C₆-alkylene-, i.e. the 3-12-membered heterocycloalkyl moiety may not be directly bound to the compound according to general formula (I) but may be connected thereto through a —C₁-C₆-alkylene-linker. Said linker may be connected to a carbon ring atom or to a hetero ring atom of the 3-12-membered heterocycloalkyl moiety. Examples include but are not limited to —CH₂-oxetane, —CH₂-pyrrolidine, —CH₂-piperidine, —CH₂-morpholine, —CH₂CH₂-oxetane, —CH₂CH₂-pyrrolidine, —CH₂CH₂-piperidine, and —CH₂CH₂-morpholine.

According to the invention, unless expressly stated otherwise, the 3-12-membered heterocycloalkyl moiety can be unsubstituted, mono- or polysubstituted. Examples of substituted 3-12-membered heterocycloalkyl moieties include but are not limited to 2-carboxamido-N-pyrrolidinyl-, 3,4-dihydroxy-N-pyrrolidinyl, 3-hydroxy-N-pyrimidinyl, 3,4-dihydroxy-N-pyrimidinyl, 3-oxo-N-piperazinyl, -tetrahydro-2H-thiopyranyl dioxide and thiomorpholinyl dioxide.

According to the invention, “6-14-membered aryl moiety” means an aromatic, monocyclic, bicyclic or tricyclic moiety comprising 6 to 14 ring carbon atoms but no heteroatoms in the ring. Examples of preferred 6-14-membered aryl moieties according to the invention include but are not limited to benzene, naphthalene, anthracen, and phenanthren. The 6-14-membered aryl moiety, which is bonded to the compound according to the invention, in its periphery may optionally be condensed with a 3-12-membered cycloalkyl moiety, saturated or unsaturated, unsubstituted, mono- or polysubstituted; and/or with a 3-12-membered heterocycloalkyl moiety, saturated or unsaturated, unsubstituted, mono- or polysubstituted; and/or with a 5-14-membered heteroaryl moiety, unsubstituted, mono- or polysubstituted. Under these circumstances, the ring atoms of the condensed moieties are not included in the 6 to 14 ring carbon atoms of the 6-14-membered heterocycloalkyl moieties. Examples of 6-14-membered aryl moieties condensed with 3-12-membered cycloalkyl moieties include but are not limited to 2,3-dihydro-1H-indene and tetraline, which in each case are connected through the 6-14-membered aryl moiety. An example of a 6-14-membered aryl moiety condensed with a 3-12-membered heterocycloalkyl moiety includes but is not limited to 1,2,3,4-tetrahydroquinoline, which is connected through the 6-14-membered aryl moiety. Examples of 6-14-membered aryl moieties condensed with 5-14-membered heteroaryl moieties include but are not limited to quinoline, isoquinoline, phenazine and phenoxacine, which in each case are connected through the 6-14-membered aryl moiety.

According to the invention, the 6-14-membered aryl moiety may optionally be connected through —C₁-C₆-alkylene-, i.e. the 6-14-membered aryl moiety may not be directly bound to the compound according to general formula (I) but may be connected thereto through a —C₁-C₆-alkylene-linker. Said linker may be connected to a carbon ring atom or to a hetero ring atom of the 6-14-membered aryl moiety. Examples include but are not limited to —CH₂—C₆H, —CH₂CH₂—C₆H5 and —CH═CH—C₆H5.

According to the invention, unless expressly stated otherwise, the 6-14-membered aryl moiety can be unsubstituted, mono- or polysubstituted. Examples of substituted 6-14-membered aryl moieties include but are not limited to 2-fluorophenyl, 3-fluorophenyl, 2-methoxyphenyl and 3-methoxyphenyl.

According to the invention, “5-14-membered heteroaryl moiety” means an aromatic, monocyclic, bicyclic or tricyclic moiety comprising 6 to 14 ring atoms, wherein each cycle comprises independently of one another 1, 2, 3, 4 or more heteroatoms independently of one another selected from the group consisting of nitrogen, oxygen and sulfur, whereas the remaining ring atoms are carbon atoms, and whereas bicyclic or tricyclic systems may share common heteroatom(s). Examples of preferred 5-14-membered heteroaryl moieties according to the invention include but are not limited to pyrrole, pyrazole, imidazole, triazole, tetrazole, furane, thiophene, oxazole, isoxazole, thiazole, isothiazole, pyridine, pyridazine, pyrimidine, pyrazine, indolicine, 9H-chinolicine, 1,8-naphthyridine, purine, imidazo[1,2-a]pyrazine, and pteridine. The 5-14-membered heteroaryl moiety, which is bonded to the compound according to the invention, in its periphery may optionally be condensed with a 3-12-membered cycloalkyl moiety, saturated or unsaturated, unsubstituted, mono- or polysubstituted; and/or with a 3-12-membered heterocycloalkyl moiety, saturated or unsaturated, unsubstituted, mono- or polysubstituted; and/or with a 6-14-membered aryl moiety, unsubstituted, mono- or polysubstituted. Under these circumstances, the ring atoms of the condensed moieties are not included in the 6 to 14 ring carbon atoms of the 6-14-membered heterocycloalkyl moieties. Examples of 5-14-membered heteroaryl moieties condensed with 3-12-membered cycloalkyl moieties include but are not limited to 5,6,7,8-tetrahydroquinoline and 5,6,7,8-tetrahydroquinazoline, which in each case are connected through the 5-14-membered heteroaryl moiety. An examples of a 5-14-membered heteroaryl moiety condensed with a 3-12-membered heterocycloalkyl moiety includes but is not limited to 5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyrazine, which is connected through the 5-14-membered heteroaryl moiety. Examples of 5-14-membered heteroaryl moieties condensed with 6-14-membered aryl moieties include but are not limited to quinoline, isoquinoline, phenazine and phenoxacine, which in each case are connected through the 5-14-membered heteroaryl moiety.

According to the invention, the 5-14-membered heteroaryl moiety may optionally be connected through —C₁-C₆-alkylene-, i.e. the 5-14-membered heteroaryl moiety may not be directly bound to the compound according to general formula (I) but may be connected thereto through a —C₁-C₆-alkylene-linker. Said linker may be connected to a carbon ring atom or to a hetero ring atom of the 5-14-membered heteroaryl moiety. Examples include but are not limited to —CH₂-oxazole, —CH₂-isoxazole, —CH₂-imidazole, —CH₂-pyridine, —CH₂-pyrimidine, —CH₂-pyridazine, —CH₂CH₂-oxazole, —CH₂CH₂-isoxazole, —CH₂CH₂-imidazole, —CH₂CH₂-pyridine, —CH₂CH₂-pyrimidine, and —CH₂CH₂-pyridazine.

According to the invention, unless expressly stated otherwise, the 5-14-membered heteroaryl moiety can be unsubstituted, mono- or polysubstituted. Examples of 5-14-membered heteroaryl moieties include but are not limited to 2-methoxy-4-pyridinyl, 2-methoxy-5-pyridinyl, 3-methoxy-4-pyridinyl, 3-methoxy-6-pyridinyl, 4-methoxy-2-pyridinyl, 2-methylsulfonyl-5-pyridinyl, 3-methylsulfonyl-6-pyridinyl, 3-methoxy-6-pyridazinyl, 2-nitrilo-5-pyrimidinyl, 4-hydroxy-2-pyrimidinyl, 4-methoxy-pyrimidinyl, and 2-methoxy-6-pyrazinyl.

Preferably, the compound according to the invention has a structure according to general formula (I′)

wherein R¹ to R⁵, R¹¹ to R²⁰ are defined as above,

or a physiologically acceptable salt thereof.

In one preferred embodiment, the excess of the cis-isomer so designated is at least 50% de, more preferably at least 75% de, yet more preferably at least 90% de, most preferably at least 95% de and in particular at least 99% de.

In a preferred embodiment, the compound according to the invention has a structure according to general formula (IX) or (X)

wherein R² means —H or —CH₃; R³ means -phenyl or -3-fluorophenyl; R^(C) means —H or —OH; R^(E) means —H, —CH₃, —F, —CF₃, -cyclopropyl, -aziridinyl, —OH; —O—C₁-C₄-alkyl; —OCF₃; —C₁-C₄-alkyl-CO₂H; —O—C₁-C₄-alkyl-C(═O)O—C₁-C₄-alkyl; or —O—C₁-C₄-alkyl-CONH₂; R^(F) means —CF₃, -cyclopropyl, —S(═O)₂CH₃, —NH₂; —NHC₁-C₄-alkyl; —N(C₁-C₄-alkyl)₂; —NHC₁-C₄-alkyl-OH; —NCH₃C₁-C₄-alkyl-OH; —NH—C₁-C₄-alkyl-C(═O)NH₂; —NCH₃—C₁-C₄-alkyl-C(═O)NH₂; —NHC(═O)—C₁-C₄-alkyl; —NCH₃C(═O)—C₁-C₄-alkyl; -6-14-membered aryl, unsubstituted, mono- or polysubstituted; or -5-14-membered heteroaryl, unsubstituted, mono- or polysubstituted; U means ═CH— or ═N—; and V means ═CH— or ═N—; or a physiologically acceptable salt thereof

In a preferred embodiment, the compound according to the invention has a structure according to general formula (XI)

wherein R² means —H or —CH₃; R³ means -phenyl or -3-fluorophenyl; R^(H) means —CN; —C₁-C₄-alkyl; —CF₃; —C₁-C₄-alkyl-C(═O)NH₂; —C₁-C₄-alkyl-S(═O)₂—C₁-C₄-alkyl; —C(═O)—C₁-C₄-alkyl; —C(═O)OH; —C(═O)O—C₁-C₄-alkyl; —C(═O)NH₂; —C(═O)NHC₁-C₄-alkyl; —C(═O)N(C₁-C₄-alkyl)₂; —C(═O)NH(C₁-C₄-alkyl-OH); —C(═O)N(C₁-C₄-alkyl)(C₁-C₄-alkyl-OH); —C(═O)NH—(CH₂CH₂O)₁₋₃₀—CH₃; -3-12-membered cycloalkyl, saturated or unsaturated, unsubstituted, mono- or polysubstituted; wherein said 3-12-membered cycloalkyl is optionally connected through —CH₂—, —NH—, —NCH₃—, —NH—(CH₂)₁₋₃—, —NCH₃(CH₂)₁₋₃—, —(C═O)—, —NHC(═O)—, —NCH₃C(═O)—, —C(═O)NH—(CH₂)₁₋₃—, —C(═O)NCH₃—(CH₂)₁₋₃—; or -3-12-membered heterocycloalkyl, saturated or unsaturated, unsubstituted, mono- or polysubstituted; 6-14-membered aryl, unsubstituted, mono- or polysubstituted; wherein said 3-12-membered heterocycloalkyl is optionally connected through —CH₂—, —NH—, —NCH₃—, —NH—(CH₂)₁₋₃—, —NCH₃(CH₂)₁₋₃—, —(C═O)—, —NHC(═O)—, —NCH₃C(═O)—, —C(═O)NH—(CH₂)₁₋₃—, —C(═O)NCH₃—(CH₂)₁₋₃—; R^(G) means —CF₃, —S(═O)₂CH₃; —NH₂; —NHC₁-C₄-alkyl; —N(C₁-C₄-alkyl)₂; —NHC₁-C₄-alkyl-OH; —NCH₃C₁-C₄-alkyl-OH; —NH—C₁-C₄-alkyl-C(═O)NH₂; —NCH₃—C₁-C₄-alkyl-C(═O)NH₂; —NHC(═O)—C₁-C₄-alkyl; —NCH₃C(═O)—C₁-C₄-alkyl; -3-12-membered cycloalkyl, saturated or unsaturated, unsubstituted, mono- or polysubstituted; wherein said 3-12-membered cycloalkyl is optionally connected through —CH₂—, —NH—, —NCH₃—, —NH—(CH₂)₁₋₃—, —NCH₃(CH₂)₁₋₃—, —(C═O)—, —NHC(═O)—, —NCH₃C(═O)—, —C(═O)NH—(CH₂)₁₋₃—, —C(═O)NCH₃—(CH₂)₁₋₃—; or -3-12-membered heterocycloalkyl, saturated or unsaturated, unsubstituted, mono- or polysubstituted; 6-14-membered aryl, unsubstituted, mono- or polysubstituted; wherein said 3-12-membered heterocycloalkyl is optionally connected through —CH₂—, —NH—, —NCH₃—, —NH—(CH₂)₁₋₃—, —NCH₃(CH₂)₁₋₃—, —(C═O)—, —NHC(═O)—, —NCH₃C(═O)—, —C(═O)NH—(CH₂)₁₋₃—, —C(═O)NCH₃—(CH₂)₁₋₃—; or a physiologically acceptable salt thereof.

In a preferred embodiment, the compounds according to the invention are in the form of the free bases.

In another preferred embodiment, the compounds according to the invention are in the form of the physiologically acceptable salts.

For the purposes of the description, a “salt” is to be understood as being any form of the compound in which it assumes an ionic form or is charged and is coupled with a counter-ion (a cation or anion) or is in solution. The term is also to be understood as meaning complexes of the compound with other molecules and ions, in particular complexes which are associated via ionic interactions. Preferred salts are physiologically acceptable, in particular physiologically acceptable salts with anions or acids or also a salt formed with a physiologically acceptable acid.

Physiologically acceptable salts with anions or acids are salts of the particular compound in question with inorganic or organic acids which are physiologically acceptable, in particular when used in humans and/or mammals. Examples of physiologically acceptable salts of particular acids include but are not limited to salts of hydrochloric acid, sulfuric acid, and acetic acid.

The invention also includes isotopic isomers of a compound according to the invention, wherein at least one atom of the compound is replaced by an isotope of the respective atom which is different from the naturally predominantly occurring isotope, as well as any mixtures of isotopic isomers of such a compound. Preferred isotopes are ²H (deuterium), ³H (tritium), ¹³C and ¹⁴C.

Certain compounds according to the invention are useful for modulating a pharmacodynamic response from one or more opioid receptors (mu, delta, kappa, NOP/ORL-1) either centrally or peripherally, or both. The pharmacodynamic response may be attributed to the compound either stimulating (agonizing) or inhibiting (antagonizing) the one or more receptors. Certain compounds according to the invention may antagonize one opioid receptor, while also agonizing one or more other receptors. Compounds according to the invention having agonist activity may be either full agonists or partial agonists.

As used herein, compounds that bind to receptors and mimic the regulatory effects of endogenous ligands are defined as “agonists”. Compounds that bind to a receptor but produce no regulatory effect, but rather block the binding of ligands to the receptor, are defined as “antagonists”.

In certain embodiments, the compounds according to the invention are agonists at the mu opioid (MOP) and/or kappa opioid (KOP) and/or delta opioid (DOP) and/or nociceptin opioid (NOP/ORL-1) receptors.

The compounds according to the invention potently bind to the MOP and/or KOP and/or DOP and/or NOP receptors.

The compounds according to the invention can be modulators at the MOP and/or KOP and/or DOP and/or NOP receptors, and therefore the compounds according to the invention can be used/administered to treat, ameliorate, or prevent pain.

In some embodiments, the compounds according to the invention are agonists of one or more opioid receptors. In some embodiments, the compounds according to the invention are agonists of the MOP and/or KOP and/or DOP and/or NOP receptors.

In some embodiments, the compounds according to the invention are antagonists of one or more opioid receptors. In some embodiments, the compounds according to the invention are antagonists of the MOP and/or KOP and/or DOP and/or NOP receptors.

In some embodiments, the compounds according to the invention have both, (i) agonist activity at the NOP receptor; and (ii) agonist activity at one or more of the MOP, KOP, and DOP receptors.

In some embodiments, the compounds according to the invention have both, (i) agonist activity at the NOP receptor; and (ii) antagonist activity at one or more of the MOP, KOP, and DOP receptors.

In some embodiments, the compounds according to the invention have both, (i) antagonist activity at the NOP receptor; and (ii) agonist activity at one or more of the MOP, KOP, and DOP receptors.

In some embodiments, the compounds according to the invention have both, (i) antagonist activity at the NOP receptor; and (ii) antagonist activity at one or more of the MOP, KOP, and DOP receptors.

In some embodiments, preferably with respect to receptors of the peripheral nervous system, the compounds according to the invention have selective agonist activity at the NOP receptor. In some embodiments, preferably with respect to receptors of the peripheral nervous system, the compounds according to the invention

-   -   have agonist activity at the NOP receptor, but no significant         activity at the MOP receptor;     -   have agonist activity at the NOP receptor, but no significant         activity at the KOP receptor;     -   have agonist activity at the NOP receptor, but no significant         activity at the DOP receptor;     -   have agonist activity at the NOP receptor, but no significant         activity at the MOP receptor as well as no significant activity         at the KOP receptor;     -   have agonist activity at the NOP receptor, but no significant         activity at the MOP receptor as well as no significant activity         at the DOP receptor; or     -   have agonist activity at the NOP receptor, but no significant         activity at the MOP receptor as well as no significant activity         at the KOP receptor as well as no significant activity at the         DOP receptor.

In some embodiments, preferably with respect to receptors of the peripheral nervous system, the compounds according to the invention have balanced agonist activity at the NOP receptor as well as at the MOP receptor. In some embodiments, preferably with respect to receptors of the peripheral nervous system, the compounds according to the invention

-   -   have agonist activity at the NOP receptor as well as agonist         activity at the MOP receptor;     -   have agonist activity at the NOP receptor as well as agonist         activity at the MOP receptor as well as agonist activity at the         KOP receptor;     -   have agonist activity at the NOP receptor as well as agonist         activity at the MOP receptor as well as agonist activity at the         DOP receptor;     -   can be regarded as opioid pan agonists, i.e. have agonist         activity at the NOP receptor as well as agonist activity at the         MOP receptor as well as agonist activity at the KOP receptor as         well as agonist activity at the DOP receptor;     -   have agonist activity at the NOP receptor as well as agonist         activity at the MOP receptor, but no significant activity at the         KOP receptor;     -   have agonist activity at the NOP receptor as well as agonist         activity at the MOP receptor, but no significant activity at the         DOP receptor; or     -   have agonist activity at the NOP receptor as well as agonist         activity at the MOP receptor, but no significant activity at the         KOP receptor as well as no significant activity at the DOP         receptor.

In some embodiments, preferably with respect to receptors of the peripheral nervous system, the compounds according to the invention have balanced agonist activity at the NOP receptor as well as at the KOP receptor. In some embodiments, preferably with respect to receptors of the peripheral nervous system, the compounds according to the invention

-   -   have agonist activity at the NOP receptor as well as agonist         activity at the KOP receptor;     -   have agonist activity at the NOP receptor as well as agonist         activity at the KOP receptor as well as agonist activity at the         MOP receptor;     -   have agonist activity at the NOP receptor as well as agonist         activity at the KOP receptor as well as agonist activity at the         DOP receptor;     -   have agonist activity at the NOP receptor as well as agonist         activity at the KOP receptor, but no significant activity at the         MOP receptor;     -   have agonist activity at the NOP receptor as well as agonist         activity at the KOP receptor, but no significant activity at the         DOP receptor; or     -   have agonist activity at the NOP receptor as well as agonist         activity at the KOP receptor, but no significant activity at the         MOP receptor as well as no significant activity at the DOP         receptor.

In some embodiments, preferably with respect to receptors of the peripheral nervous system, the compounds according to the invention have balanced agonist activity at the NOP receptor as well as at the DOP receptor. In some embodiments, preferably with respect to receptors of the peripheral nervous system, the compounds according to the invention

-   -   have agonist activity at the NOP receptor as well as agonist         activity at the DOP receptor;     -   have agonist activity at the NOP receptor as well as agonist         activity at the DOP receptor, but no significant activity at the         MOP receptor;     -   have agonist activity at the NOP receptor as well as agonist         activity at the DOP receptor, but no significant activity at the         KOP receptor; or     -   have agonist activity at the NOP receptor as well as agonist         activity at the DOP receptor, but no significant activity at the         MOP receptor as well as no significant activity at the KOP         receptor.

In some embodiments, preferably with respect to receptors of the peripheral nervous system, the compounds according to the invention have selective agonist activity at the KOP receptor. In some embodiments, preferably with respect to receptors of the peripheral nervous system, the compounds according to the invention

-   -   have agonist activity at the KOP receptor, but no significant         activity at the MOP receptor;     -   have agonist activity at the KOP receptor, but no significant         activity at the NOP receptor;     -   have agonist activity at the KOP receptor, but no significant         activity at the DOP receptor;     -   have agonist activity at the KOP receptor, but no significant         activity at the MOP receptor as well as no significant activity         at the NOP receptor;     -   have agonist activity at the KOP receptor, but no significant         activity at the MOP receptor as well as no significant activity         at the DOP receptor; or     -   have agonist activity at the KOP receptor, but no significant         activity at the MOP receptor as well as no significant activity         at the NOP receptor as well as no significant activity at the         DOP receptor.

In some embodiments, preferably with respect to receptors of the peripheral nervous system, the compounds according to the invention have agonist activity at the MOP receptor, agonist activity at the KOP receptor, and antagonist activity at the DOP receptor. In some embodiments, preferably with respect to receptors of the peripheral nervous system, the compounds according to the invention

-   -   have agonist activity at the MOP receptor as well as agonist         activity at the KOP receptor as well as antagonist activity at         the DOP receptor;     -   have agonist activity at the MOP receptor as well as agonist         activity at the KOP receptor as well as antagonist activity at         the DOP receptor as well as agonist activity at the NOP         receptor;     -   have agonist activity at the MOP receptor as well as agonist         activity at the KOP receptor as well as antagonist activity at         the DOP receptor as well as antagonist activity at the NOP         receptor; or     -   have agonist activity at the MOP receptor as well as agonist         activity at the KOP receptor as well as antagonist activity at         the DOP receptor, no significant activity at the NOP receptor.

In some embodiments, preferably with respect to receptors of the central nervous system, the compounds according to the invention have selective agonist activity at the NOP receptor. In some embodiments, preferably with respect to receptors of the central nervous system, the compounds according to the invention

-   -   have agonist activity at the NOP receptor, but no significant         activity at the MOP receptor;     -   have agonist activity at the NOP receptor, but no significant         activity at the KOP receptor;     -   have agonist activity at the NOP receptor, but no significant         activity at the DOP receptor;     -   have agonist activity at the NOP receptor, but no significant         activity at the MOP receptor as well as no significant activity         at the KOP receptor;     -   have agonist activity at the NOP receptor, but no significant         activity at the MOP receptor as well as no significant activity         at the DOP receptor; or     -   have agonist activity at the NOP receptor, but no significant         activity at the MOP receptor as well as no significant activity         at the KOP receptor as well as no significant activity at the         DOP receptor.

In some embodiments, preferably with respect to receptors of the central nervous system, the compounds according to the invention have selective antagonist activity at the NOP receptor. In some embodiments, preferably with respect to receptors of the central nervous system, the compounds according to the invention

-   -   have antagonist activity at the NOP receptor, but no significant         activity at the MOP receptor;     -   have antagonist activity at the NOP receptor, but no significant         activity at the KOP receptor;     -   have antagonist activity at the NOP receptor, but no significant         activity at the DOP receptor;     -   have antagonist activity at the NOP receptor, but no significant         activity at the MOP receptor as well as no significant activity         at the KOP receptor;     -   have antagonist activity at the NOP receptor, but no significant         activity at the MOP receptor as well as no significant activity         at the DOP receptor; or     -   have antagonist activity at the NOP receptor, but no significant         activity at the MOP receptor as well as no significant activity         at the KOP receptor as well as no significant activity at the         DOP receptor.

In some embodiments, preferably with respect to receptors of the central nervous system, the compounds according to the invention have antagonist activity at the NOP receptor as well as agonist activity at the DOP receptor. In some embodiments, preferably with respect to receptors of the central nervous system, the compounds according to the invention

-   -   have antagonist activity at the NOP receptor as well as agonist         activity at the DOP receptor;     -   have antagonist activity at the NOP receptor as well as agonist         activity at the DOP receptor, but no significant activity at the         MOP receptor;     -   have antagonist activity at the NOP receptor as well as agonist         activity at the DOP receptor, but no significant activity at the         KOP receptor; or     -   have antagonist activity at the NOP receptor as well as agonist         activity at the DOP receptor, but no significant activity at the         MOP receptor as well as no significant activity at the KOP         receptor.

For the purpose of the specification, “no significant activity” means that the activity (agonist/antagonist) of the given compound at this receptor is lower by a factor of 1000 or more compared to its activity (agonist/antagonist) at one or more of the other opioid receptors.

A further aspect of the invention relates to the compounds according to the invention as medicaments.

A further aspect of the invention relates to the compounds according to the invention for use in the treatment of pain. A further aspect of the invention relates to a method of treating pain comprising the administration of a pain alleviating amount of a compound according to the invention to a subject in need thereof, preferably to a human. The pain is preferably acute or chronic. The pain is preferably nociceptive or neuropathic.

A further aspect of the invention relates to the compounds according to the invention for use in the treatment of neurodegenerative disorders, neuroinflammatory disorders, neuropsychiatric disorders, and substance abuse/dependence. A further aspect of the invention relates to a method of treating any one of the aforementioned disorders, diseases or conditions comprising the administration of a therapeutically effective amount of a compound according to the invention to a subject in need thereof, preferably to a human.

Another aspect of the invention relates to a pharmaceutical composition which contains a physiologically acceptable carrier and at least one compound according to the invention.

Preferably, the composition according to the invention is solid, liquid or pasty; and/or contains the compound according to the invention in an amount of from 0.001 to 99 wt. %, preferably from 1.0 to 70 wt. %, based on the total weight of the composition.

The pharmaceutical composition according to the invention can optionally contain suitable additives and/or auxiliary substances and/or optionally further active ingredients.

Examples of suitable physiologically acceptable carriers, additives and/or auxiliary substances are fillers, solvents, diluents, colorings and/or binders. These substances are known to the person skilled in the art (see H. P. Fiedler, Lexikon der Hilfsstoffe fur Pharmazie, Kosmetik and angrenzende Gebiete, Editio Cantor Aulendoff).

The pharmaceutical composition according to the invention contains the compound according to the invention in an amount of preferably from 0.001 to 99 wt. %, more preferably from 0.1 to 90 wt. %, yet more preferably from 0.5 to 80 wt. %, most preferably from 1.0 to 70 wt. % and in particular from 2.5 to 60 wt. %, based on the total weight of the pharmaceutical composition.

The pharmaceutical composition according to the invention is preferably for systemic, topical or local administration, preferably for oral administration.

Another aspect of the invention relates to a pharmaceutical dosage form which contains the pharmaceutical composition according to the invention.

In one preferred embodiment, the pharmaceutical dosage form according to the invention is produced for administration twice daily, for administration once daily or for administration less frequently than once daily. Administration is preferably systemic, in particular oral.

The pharmaceutical dosage form according to the invention can be administered, for example, as a liquid dosage form in the form of injection solutions, drops or juices, or as a semi-solid dosage form in the form of granules, tablets, pellets, patches, capsules, plasters/spray-on plasters or aerosols. The choice of auxiliary substances etc. and the amounts thereof to be used depend on whether the form of administration is to be administered orally, perorally, parenterally, intravenously, intraperitoneally, intradermally, intramuscularly, intranasally, buccally, rectally or locally, for example to the skin, the mucosa or into the eyes.

Pharmaceutical dosage forms in the form of tablets, dragees, capsules, granules, drops, juices and syrups are suitable for oral administration, and solutions, suspensions, readily reconstitutable dry preparations and also sprays are suitable for parenteral, topical and inhalatory administration. Compounds according to the invention in a depot, in dissolved form or in a plaster, optionally with the addition of agents promoting penetration through the skin, are suitable percutaneous administration preparations.

The amount of the compounds according to the invention to be administered to the patient varies in dependence on the weight of the patient, on the type of administration, on the indication and on the severity of the disease. Usually, from 0.00005 mg/kg to 50 mg/kg, preferably from 0.001 mg/kg to 10 mg/kg, of at least one compound according to the invention is administered.

Another aspect of the invention relates to a process for the preparation of the compounds according to the invention. Suitable processes for the synthesis of the compounds according to the invention are known in principle to the person skilled in the art.

Preferred synthesis routes are described below:

The compounds according to the invention can be obtained via different synthesis routes. Depending on the synthesis route, different intermediates are prepared and subsequently further reacted.

In a preferred embodiment, the synthesis of the compounds according to the invention proceeds via a synthesis route which comprises the preparation of an intermediate according to general formula (IIIa):

wherein R¹, R² and R³ are defined as above.

In another preferred embodiment, the synthesis of the compounds according to the invention proceeds via a synthesis route which comprises the preparation of an intermediate according to general formula (IIIb):

wherein R¹, R² and R³ are defined as above and PG is a protecting group.

Preferably the protecting group is -p-methoxybenzyl. Therefore, in another preferred embodiment, the synthesis of the compounds according to the invention proceeds via a synthesis route which comprises the preparation of an intermediate according to general formula (IIIc):

wherein R¹, R² and R³ are defined as above.

As already indicated, in general formula (IIIc), the -p-methoxybenzyl moiety represents a protecting group which can be cleaved in the course of the synthesis route.

In yet another preferred embodiment, the synthesis of the compounds according to the invention proceeds via a synthesis route which comprises the preparation of

-   -   an intermediate according to general formula (IIIa) and         according to general formula (IIIb); or     -   an intermediate according to general formula (IIIa) and         according to general formula (IIIc); or     -   an intermediate according to general formula (IIIb) and         according to general formula (IIIc); or     -   an intermediate according to general formula (IIIa), according         to general formula (IIIb) and according to general formula         (IIIc).

The following examples further illustrate the invention but are not to be construed as limiting its scope.

EXAMPLES

“RT” means room temperature (23±7° C.), “M” are indications of concentration in mol/l, “aq.” means aqueous, “sat.” means saturated, “sol.” means solution, “conc.” means concentrated.

Further Abbreviations

brine saturated aqueous sodium chloride solution CC column chromatography cHex cyclohexane dba dibenzylideneacetone DCM dichloromethane

DIPEA N,N-diisopropylethylamine DMF N,N-dimethylformamide

Et ethyl ether diethyl ether EE ethyl acetate EtOAc ethyl acetate EtOH ethanol h hour(s) H₂O water HATU O-(7-aza-benzotriazol-1-yl)-N,N,N′,N′-tetramethyluroniumhexafluorophosphate LDA lithium diisoproylamide Me methyl m/z mass-to-charge ratio MeOH methanol MeCN acetonitrile min minutes MS mass spectrometry

NBS N-bromosuccinimide NIS N-iodosuccinimide

NEt₃ triethylamine PE petroleum ether (60-80° C.) RM reaction mixture RT room temperature TFA trifluoroacetic acid T3P 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphorinane-2,4,6-trioxide tBME tert-butyl methyl ether THF tetrahydrofurane v/v volume to volume w/w weight to weight Xantphos 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene

The yields of the compounds prepared were not optimised. All temperatures are uncorrected.

All starting materials, which are not explicitly described, were either commercially available (the details of suppliers such as for example Acros, Aldrich, Bachem, Butt park, Enamine, Fluka, Lancaster, Maybridge, Merck, Sigma, TCI, Oakwood, etc. can be found in the Symyx® Available Chemicals Database of MDL, San Ramon, US or the SciFinder® Database of the ACS, Washington D.C., US, respectively, for example) or the synthesis thereof has already been described precisely in the specialist literature (experimental guidelines can be found in the Reaxys® Database of Elsevier, Amsterdam, NL or the SciFinder® Database of the ACS, Washington D.C., US, respectively, for example) or can be prepared using the conventional methods known to the person skilled in the art.

The mixing ratios of solvents or eluents for chromatography are specified in v/v.

All the intermediate products and exemplary compounds were analytically characterised by mass spectrometry (MS, m/z for [M+H]⁺). In addition ¹H-NMR and ¹³C spectroscopy was carried out for all the exemplary compounds and selected intermediate products.

Remark Regarding Stereochemistry

CIS refers to the relative configuration of compounds described herein, in which both nitrogen atoms are drawn on the same face of the cyclohexane ring as described in the following exemplary structure. Two depictions are possible:

TRANS refers to compounds, in which both nitrogen atoms are on opposite faces of the cyclohexane ring as described in the following exemplary structure. Two depictions are possible:

Synthesis of Intermediates Synthesis of INT-600: 5-(cis-8-(Dimethylamino)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)pyrimidine-2-carbonitrile

Cs₂CO₃ (1.1 g, 3.66 mmol) was added to the solution of CIS-8-(dimethylamino)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one (INT-976) (0.5 g, 1.83 mmol), Xanthphos (0.158 g, 0.274 mmol), Pd₂(dba)₃ (0.083 g, 0.091 mmol) and 5-bromopyrimidine-2-carbonitrile (0.52 g, 2.74 mmol) in 1,4-dioxane (20 mL) under argon atmosphere. The reaction mixture was stirred for 16 h at 90° C., then cooled to RT and concentrated under reduced pressure. The residue was suspended in EtOAc (20 mL) and filtered through a plug of celite. The filtrate was concentrated under reduced pressure and the resulting residue was purified by flash chromatography on silica gel to afford 5-(cis-8-(dimethylamino)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)pyrimidine-2-carbonitrile (INT-600) (0.4 g) as a white solid.

Synthesis of INT-799: CIS-8-Dimethylamino-1-[(1-hydroxy-cyclobutyl)-methyl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one

Step 1: CIS-1-((1-(benzyloxy)cyclobutyl)methyl)-3-(3,4-dimethoxybenzyl)-8-(dimethylamino)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one

NaOH (1.42 g, 35.5 mmol) was added to a solution of CIS-3-(3,4-dimethoxybenzyl)-8-(dimethylamino)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one (INT-794) (3 g, 7.09 mmol) in DMSO (90 mL) under argon atmosphere and the reaction mixture was stirred at 80° C. for 30 min. ((1-(Bromomethyl)cyclobutoxy)methyl)benzene (5.4 g, 21.3 mmol) was added and stirring was continued for 2 days at 80° C. The reaction completion was monitored by TLC. The reaction mixture was diluted with water (500 mL) and extracted with diethyl ether (4×300 mL). The combined organic extracts were dried over anhydrous Na₂SO₄ and concentrated under reduced pressure. The residue was purified by column chromatography (230-400mesh silica gel; 65-70% EtOAc in petroleum ether as eluent) to afford 2.5 g (59%) of CIS-1-((1-(benzyloxy)cyclobutyl)methyl)-3-(3,4-dimethoxybenzyl)-8-(dimethylamino)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one (TLC system: 10% MeOH in DCM; Rf: 0.8).

Step 2: CIS-8-Dimethylamino-1-[(1-hydroxy-cyclobutyl)-methyl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one

TFA (12 mL) was added to CIS-1-((1-(benzyloxy)cyclobutyl)methyl)-3-(3,4-dimethoxybenzyl)-8-(dimethylamino)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one (2.5 g, 4.18 mmol) at 0° C. and the resulting mixture was stirred at 70° C. for 6 h. The reaction completion was monitored by LCMS. The reaction mixture was concentrated under reduced pressure. To the residue sat. aq. NaHCO₃ was added (until pH 10) and the organic product was extracted with DCM (3×150 mL). The combined organic extracts were dried over anhydrous Na₂SO₄ and concentrated under reduced pressure. The residue was purified by column chromatography (230-400mesh silica gel; 5% MeOH in DCM as eluent) to afford 500 mg (33%) of CIS-8-dimethylamino-1-[(1-hydroxy-cyclobutyl)-methyl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one (INT-799) (TLC system: 10% MeOH in DCM; Rf: 0.5). [M+H]+ 358.2

Synthesis of INT-951: CIS-1-[(8-Dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-1-yl)-methyl]-cyclobutane-1-carbonitrile

Step 1: 1-((CIS-8-(dimethylamino)-3-(4-methoxybenzyl)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-1-yl)methyl)cyclobutanecarbonitrile

NaH (50% in mineral oil) (2.44 g, 50.89 mmol) was added to a solution of CIS-8-dimethylamino-3-[(4-methoxyphenyl)-methyl]-8-phenyl-1,3-diazaspiro [4.5]decan-2-one (INT-975) (5 g, 12.72 mmol) in DMF (100 mL) at 0° C. portionwise over 10 min. 1-(Bromomethyl)cyclobutanecarbonitrile (4.4 g, 25.44 mmol) was added dropwise over 10 minutes at 0° C. The reaction mixture was allowed to stir at RT for 3 h, then quenched with water and the organic product was extracted with ethyl acetate (3×200 mL). The combined organic extracts were dried over anhydrous Na₂SO₄ and concentrated under reduced pressure to afford 5 g (crude) of 1-((CIS-8-(dimethylamino)-3-(4-methoxybenzyl)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-1-yl)methyl)cyclobutane-carbonitrile as gummy brown liquid. The material was used for the next step without further purification.

Step 2: 1-((CIS-8-(dimethylamino)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-1-yl)methyl) cyclobutanecarboxamide

TFA (100 mL) was added to 1-((CIS-8-(dimethylamino)-3-(4-methoxybenzyl)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-1-yl)methyl)cyclobutanecarbonitrile (5 g, 10.28 mmol) at 0° C. and the reaction mixture at mixture was stirred at RT for 2 days. The reaction mixture was concentrated in vacuo. To the residue sat. aq. NaHCO₃ was added (until pH 10) and the organic product was extracted with dichloromethane (3×150 mL). The combined organic extracts were dried over anhydrous Na₂SO₄ and concentrated under reduced pressure to afford 3.5 g (crude) of 1-((CIS-8-(dimethylamino)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-1-yl)methyl) cyclobutanecarboxamide. The material was used for the next step without further purification.

Step 3: 1-((cis-8-(dimethylamino)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-1-yl)methyl)cyclobutane carbonitrile

Thionyl chloride (35 mL) was added to 1-((cis-8-(dimethylamino)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-1-yl)methyl)cyclobutanecarboxamide (3.5 g, 9.11 mmol) at RT and the resulting mixture was stirred at reflux for 2h. The reaction mixture was concentrated in vacuo. To the residue sat. aq. NaHCO₃ was added (until pH 10) and the organic product was extracted with dichloromethane (3×150 mL). The combined organic layer was dried over anhydrous Na₂SO₄ and concentrated in vacuo. The residue was purified by column chromatography to afford 1.3 g (34% after three steps) of CIS-1-[(8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-1-yl)-methyl]-cyclobutane-1-carbonitrile (INT-951). [M+H]⁺ 367.2.

Synthesis of INT-952: CIS-1-(Cyclobutyl-methyl)-8-dimethylamino-8-phenyl-3-[(4-methoxyphenyl)-methyl]-1,3-diazaspiro[4.5]decan-2-one

To a solution of CIS-8-dimethylamino-3-[(4-methoxyphenyl)-methyl]-8-phenyl-1,3-diazaspiro [4.5]decan-2-one (INT-975) (10 g, 25 mmol) in THF (500 mL) was added KOtBu (7.1 g, 63 mmol) at 50° C. The reaction mixture was heated up to reflux, cyclobutylmethylbromide (11.3 g, 76 mmol) was added in one portion, and stirring was continued at reflux for 12 h. KOtBu (7.1 g) and cyclobutylmethylbromide (11.3 g) were added again. The reaction mixture was allowed to stir another 2 h at reflux, then cooled to RT, diluted with water (150 mL) and the layers partitioned. The aqueous layer was extracted with EtOAc (3×300 mL). The combined organic layers were dried over Na₂SO₄ and then concentrated in vacuo. The residue was filtered through a plug of silica gel using a DCM/MeOH (19/1 v/v) mixture. The filtrate was concentrated in vacuo and the resulting solid was recrystallized from hot ethanol to yield 7.8 g of CIS-1-(cyclobutyl-methyl)-8-dimethylamino-8-phenyl-3-[(4-methoxyphenyl)-methyl]-1,3-diazaspiro[4.5]decan-2-one (INT-952). [M+H]⁺ 461.3.

Synthesis of INT-953: CIS-1-(Cyclobutyl-methyl)-8-(methyl-(2-methyl-propyl)-amino)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one

Step 1: 1-Cyclobutylmethyl-3-(4-methoxy-benzyl)-9,12-dioxa-1,3-diaza-dispiro[4.2.4.2]tetradecan-2-one

To a stirred solution of 3-(4-methoxy-benzyl)-9,12-dioxa-1,3-diaza-dispiro[4.2.4.2]tetradecan-2-one (4 g, 12.04 mmol) in anhydrous DMF (60 ml) was added NaH (1.38 g, 60% dispersion in oil, 36.14 mmol) at RT. The reaction mixture was stirred for 10 min, bromomethylcyclobutane (3 ml, 26.5 mmol) was added dropwise and stirring was continued for 50 h. TLC analysis showed complete consumption of the starting material. The reaction mixture was quenched with sat. aq. NH₄Cl (50 ml) and extracted with EtOAc (3×200 ml). The combined organic phase was dried over Na₂SO₄ and concentrated under reduced pressure. The resulting residue was purified column chromatography (neutral aluminum oxide, EtOAc—petroleum ether (2:8)) to give 1-cyclobutylmethyl-3-(4-methoxy-benzyl)-9,12-dioxa-1,3-diaza-dispiro[4.2.4.2]tetradecan-2-one (2.4 g, 50%, white solid). TLC system: EtOAc—pet ether (6:4); R_(f)=0.48.

Step 2: 1-Cyclobutylmethyl-3-(4-methoxy-benzyl)-1,3-diaza-spiro[4.5]decane-2,8-dione

To a stirred solution of 1-cyclobutylmethyl-3-(4-methoxy-benzyl)-9,12-dioxa-1,3-diaza-dispiro[4.2.4.2]tetradecan-2-one (1 g, 2.5 mmol) in MeOH (7 ml) was added 10% aq. HCl (8 ml) at 0° C. The reaction mixture was warmed up to RT and stirred for 16 h. TLC analysis showed complete consumption of the starting material. The reaction mixture was quenched with sat. aq. NaHCO₃ (30 ml) and extracted with EtOAc (3×50 ml). The combined organic phase was dried over Na₂SO₄ and concentrated under reduced pressure. The resulting residue was purified by column chromatography (silica gel, 230-400 mesh, EtOAc—pet ether (1:3)→(3:7)) to give 1-cyclobutylmethyl-3-(4-methoxy-benzyl)-1,3-diaza-spiro[4.5]decane-2,8-dione (650 mg, 73%, colorless viscous oil). TLC system: EtOAc—pet ether (6:4); R_(f)=0.40.

Step 3: 1-(cyclobutylmethyl)-8-(isobutyl(methyl)amino)-3-(4-methoxybenzyl)-2-oxo-1,3-diazaspiro[4.5]decane-8-carbonitrile

To a stirred solution of N-isobutyl-N-methylamine (1.34 ml, 11.23 mmol) and MeOH/H₂O (8 ml, 1:1, v/v) was added 4N aq. HCl (1.5 ml) and the reaction mixture was stirred for 10 min at 0° C. (ice bath). A solution of 1-cyclobutylmethyl-3-(4-methoxy-benzyl)-1,3-diaza-spiro[4.5]decane-2,8-dione (1 g, 2.80 mmol) in MeOH (7 ml) and KCN (548 mg, 8.42 mmol) were added and the reaction mixture was stirred at 45° C. for 20 h. TLC analysis showed complete consumption of the starting material. The reaction mixture was diluted with water (30 ml), extracted with EtOAc (3×30 ml), the combined organic phase was dried over Na₂SO₄ and concentrated under reduced pressure to give 1-(cyclobutylmethyl)-8-(isobutyl(methyl)amino)-3-(4-methoxybenzyl)-2-oxo-1,3-diazaspiro[4.5]decane-8-carbonitrile (1.3 g, viscous yellow oil). TLC system: EtOAc—pet ether (1:1); R_(f)=0.45. The product was used for the next step without additional purification.

Step 4: CIS-1-(cyclobutylmethyl)-8-(isobutyl(methyl)amino)-3-(4-methoxybenzyl)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one

A round bottom flask containing 1-(cyclobutylmethyl)-8-(isobutyl(methyl)amino)-3-(4-methoxybenzyl)-2-oxo-1,3-diazaspiro[4.5]decane-8-carbonitrile (1.3 g, 2.81 mmol) was cooled in an ice bath (˜0° C.) and a solution of phenylmagnesium bromide (26 ml, ˜2M in THF) was added slowly at 0° C.-5° C. The ice bath was removed and the reaction mixture was stirred for 30 min, then diluted with sat. aq. NH₄Cl (25 ml) and extracted with EtOAc (4×30 ml). The combined organic phase was dried over Na₂SO₄ and concentrated under reduced pressure to give pale yellow viscous oil. This residue was purified by column chromatography (silica gel, 230-400 mesh, eluent: EtOAc—pet ether (15:85)→(2:4)) to give CIS-1-(cyclobutylmethyl)-8-(isobutyl(methyl)amino)-3-(4-methoxybenzyl)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one (135 mg, 10%, white solid). TLC system: EtOAc -pet ether (1:1); R_(f)=0.6

Step 5: CIS-1-(Cyclobutyl-methyl)-8-(methyl-(2-methyl-propyl)-amino)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one

A round bottom flask containing CIS-1-(cyclobutylmethyl)-8-(isobutyl(methyl)amino)-3-(4-methoxybenzyl)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one (130 mg, 0.25 mmol) was cooled in an ice bath and a mixture of TFA/CH₂Cl₂ (2.6 ml, 1:1, v/v) was added slowly at 0° C.-5° C. The reaction mixture was warmed to RT and stirred for 20 h, then quenched with methanolic NH₃ (10 ml, 10% in MeOH) and concentrated under reduced pressure to give pale yellow viscous oil. This residue was purified twice by column chromatography (silica gel, 230-400 mesh, eluent: MeOH—CHCl₃ (1:99)→(2:98)) to give CIS-1-(cyclobutyl-methyl)-8-(methyl-(2-methyl-propyl)-amino)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one (INT-953) (65 mg, 66%, white solid). TLC system: MeOH—CHCl₃ (5:95); R_(f)=0.25; [M+H]⁺ 384.3

Synthesis of INT-958: 4-Oxo-1-pyridin-2-yl-cyclohexane-1-carbonitrile

Step 1: Ethyl 5-cyano-2-oxo-5-(pyridin-2-yl)cyclohexanecarboxylate

KOtBu (57.0 g, 508.4 mmol) was added to the solution of 2-(pyridin-2-yl)acetonitrile (50.0 g, 423.7 mmol) and ethyl acrylate (89.0 g, 889.8 mmol) in THF (500 mL) at 0° C. and stirred for 16 h at RT. The reaction mixture was quenched with sat. aq. NH₄Cl and extracted with EtOAc (2×500 mL). The combined organic layer was washed with brine, dried over Na₂SO₄ and concentrated under reduced pressure to afford 68.0 g (60%; crude) of ethyl 5-cyano-2-oxo-5-(pyridin-2-yl)cyclohexanecarboxylate as a brown liquid (TLC system: 50% ethyl acetate in petroleum ether; Rf: 0.65).

Step 2: 4-Oxo-1-pyridin-2-yl-cyclohexane-1-carbonitrile

A solution of ethyl 5-cyano-2-oxo-5-(pyridin-2-yl)cyclohexanecarboxylate (68.0 g, 250.0 mmol) was added to a mixture of conc. aq. HCl and glacial acetic acid (170 mL/510 mL) at 0° C. The reaction mixture was heated to 100° C. for 16 h. All volatiles were evaporated under reduced pressure. The residue was diluted with sat. aq. NaHCO₃ and extracted with ethyl acetate (3×300 mL). The combined organic layer was washed with brine, dried over Na₂SO₄ and concentrated under reduced pressure to afford 44.0 g (88%) of 4-oxo-1-pyridin-2-yl-cyclohexane-1-carbonitrile INT-958 as a brown solid (TLC system: 50% ethyl acetate in pet ether; R_(f): 0.45). [M+H]⁺ 201.1

Synthesis of INT-961: 4-Dimethylamino-4-pyridin-2-yl-cyclohexan-1-one

Step 1: 8-(pyridin-2-yl)-1,4-dioxaspiro[4.5]decane-8-carbonitrile

A solution of 4-oxo-1-pyridin-2-yl-cyclohexane-1-carbonitrile (INT-958) (44.0 g, 220.0 mmol), ethylene glycol (27.0 g, 440.0 mmol) and PTSA (4.2 g, 22.0 mmol) in toluene (450 mL) was heated to 120° C. for 16 h using Dean Stark apparatus. All volatiles were evaporated under reduced pressure. The residue was diluted with sat. aq. NaHCO₃ and extracted with ethyl acetate (3×300 mL). The combined organic layer was washed with brine, dried over Na₂SO₄ and concentrated under reduced pressure to afford 45.0 g (85%) of 8-(pyridin-2-yl)-1,4-dioxaspiro[4.5]decane-8-carbonitrile as a light brown solid (TLC system: 50% ethyl acetate in petroleum ether; Rf: 0.55).

Step 2: 8-(pyridin-2-yl)-1,4-dioxaspiro[4.5]decane-8-carboxamide

Potassium carbonate (50.0 g, 368.84 mmol) and 30% aq. H₂02 (210.0 mL, 1844.2 mmol) were added to the solution of 8-(pyridin-2-yl)-1,4-dioxaspiro[4.5]decane-8-carbonitrile (45.0 g, 184.42 mmol) in DMSO (450 mL) at 0° C. and the resulting mixture was stirred at RT for 14 h. The reaction mixture was diluted with water (1.5 L) and stirred for 1 h. The precipitated solid was separated by filtration, washed with water, petroleum ether and dried under reduced pressure to get 32.0 g (66%) of 8-(pyridin-2-yl)-1,4-dioxaspiro[4.5]decane-8-carboxamide as a white solid. (TLC system: 10% MeOH in DCM R_(f): 0.35).

Step 3: methyl 8-(pyridin-2-yl)-1,4-dioxaspiro[4.5]decan-8-ylcarbamate

A mixture of 8-(pyridin-2-yl)-1,4-dioxaspiro[4.5]decane-8-carboxamide (25.0 g, 95.41 mmol), sodium hypochlorite (5 wt % aq. solution, 700 mL, 477.09 mmol) and KF—Al₂O₃ (125.0 g) in methanol (500 mL) was heated to 80° C. for 16 h. The reaction mixture was filtered through celite and the solid residue was washed with methanol. The combined filtrate was concentrated under reduced pressure. The residue was diluted with water and extracted with ethyl acetate (3×500 mL). The combined organic layer was washed with brine, dried over Na₂SO₄ and concentrated under reduced pressure to afford 18.0 g (66%) of methyl 8-(pyridin-2-yl)-1,4-dioxaspiro[4.5]decan-8-ylcarbamate as a light brown solid. (TLC system: 5% MeOH in DCM R_(f): 0.52.)

Step 4: 8-(pyridin-2-yl)-1,4-dioxaspiro[4.5]decan-8-amine

A suspension of methyl 8-(pyridin-2-yl)-1,4-dioxaspiro[4.5]decan-8-ylcarbamate (18.0 g, 61.64 mmol) in 10 wt % aq. NaOH (200 mL) was heated to 100° C. for 24 h. The reaction mixture was filtered through celite pad, the solid residue was washed with water and the combined filtrate was extracted with EtOAc (4×200 mL). The combined organic layer washed with brine, dried over Na₂SO₄ and concentrated under reduced pressure to afford 12.5 g (88%) of 8-(pyridin-2-yl)-1,4-dioxaspiro[4.5]decan-8-amine as a light brown semi-solid. (TLC system: 5% MeOH in DCM R_(f): 0.22.).

Step 5: 4-Dimethylamino-4-pyridin-2-yl-cyclohexan-1-one

Sodium cyanoborohydride (13.7 g, 0.213 mol) was added portionwise to a solution of 8-(pyridin-2-yl)-1,4-dioxaspiro[4.5]decan-8-amine (12.5 g, 53.418 mmol) and 35 wt % aq. formaldehyde (45 mL, 0.534 mol) in acetonitrile (130 mL) at 0° C. The reaction mixture was warmed up to room temperature and stirred for 16 h. The reaction mixture was quenched with sat. aq. NH₄Cl and concentrated under reduced pressure. The residue was dissolved in water and extracted with EtOAc (3×200 mL). The combined organic layer was washed with brine, dried over Na₂SO₄ and concentrated under reduced pressure to afford 10.5 g (72%) of 4-dimethylamino-4-pyridin-2-yl-cyclohexan-1-one (INT-961) as a light brown solid. (TLC system: 5% MeOH in DCM R_(f): 0.32.). [M+H]⁺ 219.1

Synthesis of INT-965: 4-Dimethylamino-4-phenyl-cyclohexan-1-one

Step 1: 8-(Dimethylamino)-1,4-dioxaspiro[4.5]decane-8-carbonitrile

Dimethylamine hydrochloride (52 g, 0.645 mol) was added to the solution of 1,4-dioxaspiro-[4.5]-decan-8-one (35 g, 0.224 mmol) in MeOH (35 mL) at RT under argon atmosphere. The solution was stirred for 10 min and 40 wt % aq. dimethylamine (280 mL, 2.5 mol) and KCN (32 g, 0.492 mol) were sequentially added. The reaction mixture was stirred for 48 h at RT, then diluted with water (100 mL) and extracted with EtOAc (2×200 mL). The combined organic layer was dried over anhydrous Na₂SO₄ and concentrated under reduced pressure to afford 44 g of 8-(dimethylamino)-1,4-dioxaspiro-[4.5]-decane-8-carbonitrile (93%) as a white solid.

Step 2: N,N-dimethyl-8-phenyl-1,4-dioxaspiro [4.5] decan-8-amine

8-(Dimethylamino)-1,4-dioxaspiro[4.5]decane-8-carbonitrile (35 g, 0.167 mol) in THF (350 mL) was added to the solution of 3M phenylmagnesium bromide in diethyl ether (556 mL, 1.67 mol) dropwise at −10° C. under argon atmosphere. The reaction mixture was stirred for 4 h at -10° C. to 0° C. and then at RT for 18 h. The reaction completion was monitored by TLC. The reaction mixture was cooled to 0° C., diluted with sat. aq. NH₄Cl (1 L) and extracted with EtOAc (2×600 mL). The combined organic layer was dried over anhydrous Na₂SO₄ and concentrated under reduced pressure to afford 60 g of, N N-dimethyl-8-phenyl-1, 4-dioxaspiro-[4.5]-decan-8-amine as a liquid.

Step 3: 4-(dimethylamino)-4-phenylcyclohexanone

A solution of N,N-dimethyl-8-phenyl-1,4-dioxaspiro[4.5]decan-8-amine (32 g, 0.123 mol) in 6N aq. HCl (320 mL) was stirred at 0° C. for 2 h and then at RT for 18 h. The reaction completion was monitored by TLC. The reaction mixture was extracted with DCM (2×150 mL). The aqueous layer was basified to pH 10 with solid NaOH and extracted with ethyl acetate (2×200 mL). The combined organic layer was dried over anhydrous Na₂SO₄ and concentrated under reduced pressure. The solid residue was washed with hexane and dried in vacuo to afford 7 g of 4-dimethylamino-4-phenyl-cyclohexan-1-one (INT-965) (25% over 2 steps) as a brown solid. [M+H]⁺ 218.1

Synthesis of INT-966: 3-[(4-Methoxyphenyl)-methyl]-1,3-diazaspiro[4.5]decane-2,8-dione

Step 1: 9,12-Dioxa-2,4-diazadispiro[4.2.4{circumflex over ( )}{8}.2{circumflex over ( )}{5}]tetradecane-1,3-dione

KCN (93.8 g, 1441.6 mmol) and (NH₄)₂CO₃ (271.8 g, 1729.9 mmol) were added to the solution of 1,4-dioxaspiro[4.5]decan-8-one (150 g, 961 mmol) in MeOH:H₂O (1:1 v/v) (1.92 L) at RT under argon atmosphere. The reaction mixture was stirred at 60° C. for 16 h. The reaction completion was monitored by TLC. The reaction mixture was cooled to 0° C., the precipitated solid was filtered off and dried in vacuo to afford 120 g (55%) of 9,12-dioxa-2,4-diazadispiro[4.2.4{circumflex over ( )}{8}.2{circumflex over ( )}{5}]tetradecane-1,3-dione. The filtrate was extracted with DCM (2×1.5 L). The combined organic layer was dried over anhydrous Na₂SO₄ and concentrated under reduced pressure to afford additional 30 g (14%) of 9,12-dioxa-2,4-diazadispiro[4.2.4{circumflex over ( )}{8}.2{circumflex over ( )}{5}]tetradecane-1,3-dione (TLC system: 10% Methanol in DCM; Rf: 0.4).

Step 2: 2-[(4-Methoxyphenyl)-methyl]-9,12-dioxa-2,4-diazadispiro[4.2.4{circumflex over ( )}{8}.2{circumflex over ( )}{5}]tetradecane-1,3-dione

Cs₂CO₃ (258.7 g, 796.1 mmol) was added to the solution of 73a (150 g, 663.4 mmol) in MeCN (1.5 L) under argon atmosphere and the reaction mixture was stirred for 30 min. A solution of p-methoxybenzyl bromide (96 mL, 663.4 mmol) was added. The reaction mixture was stirred at RT for 48 h. The reaction completion was monitored by TLC. The reaction mixture was quenched with sat. aq. NH₄Cl (1.0 L) and the organic product was extracted with EtOAc (2×1.5 L). The combined organic layer was dried over anhydrous Na₂SO₄ and concentrated under reduced pressure. The residue was washed with diethyl ether and pentane and dried under reduced pressure to afford 151 g (65%) of 2-[(4-Methoxyphenyl)-methyl]-9,12-dioxa-2,4-diazadispiro[4.2.4{circumflex over ( )}{8}.2{circumflex over ( )}{5}]tetradecane-1,3-dione as an off white solid (TLC system: 10% MeOH in DCM; R_(f): 0.6).

Step 3: 2-[(4-Methoxyphenyl)-methyl]-9,12-dioxa-2,4-diazadispiro[4.2.4{circumflex over ( )}{8}.2{circumflex over ( )}{5}]tetradecan-3-one

AlCl₃ (144.3 g, 1082.6 mmol) was added to a solution of LiAlH₄ (2M in THF) (433 mL, 866.10 mmol) in THF (4.5 L) at 0° C. under argon atmosphere and the resulting mixture was stirred at RT for 1 h. 2-[(4-Methoxyphenyl)-methyl]-9,12-dioxa-2,4-diazadispiro[4.2.4{circumflex over ( )}{8}.2{circumflex over ( )}{5}]tetradecane-1,3-dione (150 g, 433.05 mmol) was added at 0° C. The reaction mixture was stirred at RT for 16 h. The reaction completion was monitored by TLC. The reaction mixture was cooled to 0° C., quenched with sat. aq. NaHCO₃ (500 mL) and filtered through celite pad. The filtrate was extracted with EtOAc (2×2.0 L). The combined organic layer was dried over anhydrous Na₂SO₄ and concentrated in vacuo to afford 120 g (84%) of 2-[(4-methoxyphenyl)-methyl]-9,12-dioxa-2,4-diazadispiro[4.2.4{circumflex over ( )}{8}.2{circumflex over ( )}{5}]tetradecan-3-one as an off-white solid. (TLC system: 10% MeOH in DCM, R_(f): 0.5).

Step 4: 3-[(4-Methoxyphenyl)-methyl]-1,3-diazaspiro[4.5]decane-2,8-dione

A solution of 2-[(4-methoxyphenyl)-methyl]-9,12-dioxa-2,4-diazadispiro[4.2.4{circumflex over ( )}{8}.2{circumflex over ( )}{5}]tetradecan-3-one (120 g, 361.03 mmol) in 6N aq. HCl (2.4 L) was stirred at 0° C. for 2 h and then at RT for 18 h. The reaction completion was monitored by TLC. The reaction mixture was extracted with DCM (2×2.0 L). The aqueous layer was basified to pH 10 with 50% aq. NaOH and then extracted with DCM (2×2.0 L). Combined organic extracts were dried over anhydrous Na₂SO₄ and concentrated under reduced pressure. The solid residue was washed with hexane and dried in vacuo to afford 90 g of 3-[(4-Methoxyphenyl)-methyl]-1,3-diazaspiro[4.5]decane-2,8-dione (INT-966) as an off-white solid (TLC system: 10% MeOH in DCM; Rf: 0.4) [M+H]⁺ 289.11.

Synthesis of INT-971: CIS-1-(Cyclobutyl-methyl)-8-dimethylamino-8-(3-hydroxyphenyl)-3-[(4-methoxyphenyl)-methyl]-1,3-diazaspiro[4.5]decan-2-one

Step 1: CIS-8-(dimethylamino)-1-isobutyl-3-(4-methoxybenzyl)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one

In analogy to the method described for INT-951 step 1 CIS-8-Dimethylamino-8-[3-(methoxymethyloxy)-phenyl]-3-[(4-methoxyphenyl)-methyl]-1,3-diazaspiro[4.5]decan-2-one (INT-968) was converted into CIS-1-(cyclobutylmethyl)-8-(dimethylamino)-3-(4-methoxybenzyl)-8-(3-(methoxymethoxy)phenyl)-1,3-diazaspiro[4.5]decan-2-one.

Step 2: CIS-1-(Cyclobutyl-methyl)-8-dimethylamino-8-(3-hydroxyphenyl)-3-[(4-methoxyphenyl)-methyl]-1,3-diazaspiro[4.5]decan-2-one

TFA (0.2 mL) was added to the solution of CIS-1-(cyclobutylmethyl)-8-(dimethylamino)-3-(4-methoxybenzyl)-8-(3-methoxyphenyl)-1,3-diazaspiro[4.5]decan-2-one (300 mg, 0.57 mmol) in DCM (1.5 mL) at 0° C. The reaction mixture was stirred at 0° C. for 3 h. The reaction completion was monitored by TLC. The reaction mixture was quenched with sat. aq. NaHCO₃ and the organic product was extracted with DCM (3×10 mL). The combined organic extracts were dried over anhydrous Na₂SO₄ and concentrated under reduced pressure. Purification of the residue by preparative TLC (3% MeOH in DCM as mobile phase) yielded 50 mg (18%) of CIS-1-(Cyclobutyl-methyl)-8-dimethylamino-8-(3-hydroxyphenyl)-3-[(4-methoxyphenyl)-methyl]-1,3-diazaspiro[4.5]decan-2-one (INT-971) as an off white solid. (TLC system: 10% MeOH in DCM; Rf: 0.20) [M+H]⁺ 478.3

Synthesis of INT-974: CIS-8-Dimethylamino-8-(3-fluorophenyl)-3-[(4-methoxyphenyl)-methyl]-1,3-diazaspiro[4.5]decan-2-one

Step 1: 8-(dimethylamino)-3-(4-methoxybenzyl)-2-oxo-1,3-diazaspiro[4.5]decane-8-carbonitrile

Dimethylamine hydrochloride (76.4 g, 936.4 mmol) was added to a solution of 3-[(4-methoxyphenyl)-methyl]-1,3-diazaspiro[4.5]decane-2,8-dione (INT-966) (90 g, 312.13 mmol) in MeOH (180 mL) at RT under argon atmosphere. The solution was stirred for 15 min and 40 wt % aq. dimethylamine (780 mL) and KCN (48.76 g, 749.11 mmol) were sequentially added. The reaction mixture was stirred for 48 h and the completion of the reaction was monitored by NMR. The reaction mixture was diluted with water (1.0 L) and the organic product was extracted with ethyl acetate (2×2.0 L). The combined organic layer was dried over anhydrous Na₂SO₄ and concentrated under reduced pressure to afford 90 g (85%) of 8-(dimethylamino)-3-(4-methoxybenzyl)-2-oxo-1,3-diazaspiro[4.5]decane-8-carbonitrile as an off white solid (TLC system: TLC system: 10% MeOH in DCM; Rf: 0.35, 0.30).

Step 2: CIS-8-Dimethylamino-8-(3-fluorophenyl)-3-[(4-methoxyphenyl)-methyl]-1,3-diazaspiro[4.5]decan-2-one

3-Fluorophenylmagnesium bromide (M in THF) (220 mL, 219.17 mmol) was added dropwise to a solution of 8-(dimethylamino)-3-(4-methoxybenzyl)-2-oxo-1,3-diazaspiro[4.5]decane-8-carbonitrile (15 g, 43.83 mmol) in THF (300 mL) at 0° C. under argon atmosphere. The reaction mixture was stirred for 16 h at RT. The reaction completion was monitored by TLC. The reaction mixture was cooled to 0° C., quenched with sat. aq. NH₄Cl (200 mL) and the organic product was extracted with EtOAc (2×200 mL). The combined organic layer was dried over anhydrous Na₂SO₄ and concentrated under reduced pressure. The reaction was carried out in 4 batches (15 g×2 and 5 g×2) and the batches were combined for purification. Purification of the crude product by flash column chromatography on silica gel (230-400 mesh) (2 times) (0-20% methanol in DCM) eluent and subsequently by washing with pentane yielded 5.6 g (11%) of CTS-8-dimethylamino-8-(3-fluorophenyl)-3-[(4-methoxyphenyl)-methyl]-1,3-diazaspiro[4.5]decan-2-one (INT-974) as an off-white solid. (TLC system: 5% MeOH in DCM in presence of ammonia; Rf: 0.1). [M+H]⁺ 412.2

Synthesis of INT-975: CIS-8-Dimethylamino-3-[(4-methoxyphenyl)-methyl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one

KOtBu (1M in THF) (29.30 mL, 29.30 mmol) was added to the solution of CIS-8-Dimethylamino-8-phenyl-1,3-diazaspiro[4.5]decan-2-one INT-976 (8.0 g, 29.30 mmol) in THF (160 mL) under argon atmosphere and the reaction mixture was stirred for 30 min. 4-Methoxybenzyl bromide (4.23 mL, 29.30 mmol) was added and stirring was continued at RT for 4 h. The reaction completion was monitored by TLC. The reaction mixture was diluted with sat. aq. NH₄Cl (150 mL) and the organic product was extracted with EtOAc (2×150 mL). The combined organic layer was dried over anhydrous Na₂SO₄ and concentrated in vacuo. The reaction was carried out in 2 batches (8 g×2) and the batches were combined for purification. Purification of the crude product by flash column chromatography on silica gel (0-10% methanol in DCM) and subsequently by washing with pentane yielded 11 g (47%) of CIS-8-Dimethylamino-3-[(4-methoxyphenyl)-methyl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one (INT-975) as a white solid. [M+H]⁺ 394.2

Synthesis of INT-976: CIS-8-Dimethylamino-8-phenyl-1,3-diazaspiro[4.5]decan-2-one

Step 1: 8-(dimethylamino)-8-phenyl-1,3-diazaspiro[4,5]decane-2,4-dione

In a sealed tube 4-dimethylamino-4-phenyl-cyclohexan-1-one (INT-965) (2 g, 9.22 mmol) was suspended in 40 mL EtOH/H₂O (1:1 v/v) at RT under argon atmosphere. (NH₄)₂CO₃ (3.62 g, 23.04 mmol) and KCN (0.6 g, 9.22 mmol) were added. The reaction mixture was stirred at 60° C. for 18h. The reaction mixture was cooled to 0° C. and diluted with ice-water and filtered through a glass filter. The solid residue was dried under reduced pressure to afford 8-(dimethylamino)-8-phenyl-1,3-diazaspiro[4,5]decane-2,4-dione (1.8 g, 86%) as an off white crystalline solid (TLC: 80% EtOAc in hexane; Rf: 0.25).

Step 2: 8-(dimethylamino)-8-phenyl-1, 3-diazaspiro [4, 5] decan-2-one

LiAlH₄ (2M in THF) (70 mL, 139.4 mmol) was added to the solution of 8-(dimethylamino)-8-phenyl-1,3-diazaspiro[4,5]decane-2,4-dione (10 g, 34.8 mmol) in THF/Et₂O (2:1 v/v) (400 mL) at 0° C. under argon atmosphere. The reaction mixture was stirred for 4 h at 60° C. The reaction completion was monitored by TLC. The reaction mixture was cooled to 0° C., quenched with saturated Na₂SO₄ solution (100 mL) and filtered through Celite pad. The filtrate was dried over anhydrous Na₂SO₄ and concentrated in vacuo to afford 5.7 g (59%) of 8-(dimethylamino)-8-phenyl-1, 3-diazaspiro [4, 5] decan-2-one as an off white solid. (TLC system: 10% MeOH in DCM, R_(f): 0.3).

Step 3: CIS-8-Dimethylamino-8-phenyl-1,3-diazaspiro[4.5]decan-2-one

A mixture of CIS- and TRANS-8-(dimethylamino)-8-phenyl-1,3-diazaspiro[4,5]decan-2-one (8 g, 29.30 mmol) was purified by preparative chiral SFC (column: Chiralcel AS-H, 60% CO₂, 40% (0,5% DEA in MeOH)) to get 5 g of CIS-8-Dimethylamino-8-phenyl-1,3-diazaspiro[4.5]decan-2-one (INT-976) as a white solid. [M+H]⁺ 274.2.

Synthesis of INT-977: CIS-2-(8-Dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-1-yl)-acetic acid; 2,2,2-trifluoro-acetic acid salt

Step 1: CIS-2-[8-Dimethylamino-3-[(4-methoxyphenyl)-methyl]-2-oxo-8-phenyl-1,3-diazaspiro[4.5] decan-1-yl]-acetic Acid Tert-Butyl Ester

A solution of CIS-8-Dimethylamino-3-[(4-methoxyphenyl)-methyl]-8-phenyl-1,3-diazaspiro [4.5]decan-2-one (INT-975) (5.0 g, 12.7 mmol) in THF (18 mL) was cooled to 0° C. and treated with LDA solution (2M in THF/heptane/ether, 25.4 mL, 50.8 mmol). The resulting mixture was allowed to warm up to RT over 30 min. The solution was then cooled to 0° C. again and tert-butyl-bromoacetate (5.63 mL, 38.1 mmol) was added. The reaction mixture was stirred at RT for 16 h, quenched with water and extracted with DCM (3×). The combined organic layers were dried over Na₂SO₄, filtered and concentrated under reduced pressure. Purification of the residue by column chromatography on silica gel provided CIS-2-[8-dimethylamino-3-[(4-methoxyphenyl)-methyl]-2-oxo-8-phenyl-1,3-diazaspiro[4.5] decan-1-yl]-acetic acid tert-butyl ester (4.4 g).

Step 2: cis-2-(8-Dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-1-yl)-acetic Acid Trifluoroacetic Acid Salt

CIS-2-[8-Dimethylamino-3-[(4-methoxyphenyl)-methyl]-2-oxo-8-phenyl-1,3-diazaspiro[4.5] decan-1-yl]-acetic acid tert-butyl ester (200 mg, 0.4 mmol) was dissolved in TFA (5 mL) and heated to reflux overnight. After cooling to RT all volatiles are removed in vacuo. The residue was taken up in THF (1 mL) and added dropwise to diethyl ether (20 mL). The resulting precipitate was filtered off and dried under reduced pressure to give CTS-2-(8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-1-yl)-acetic acid; 2,2,2-trifluoro-acetic acid salt (INT-977) (119 mg) as a white solid. [M+H]⁺ 332.2

Synthesis of INT-978: CIS-2-(8-Dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-1-yl)-N,N-dimethyl-acetamide

CIS-2-(8-Dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-1-yl)-acetic acid (INT-977) trifluoroacetic acid salt (119 mg, 0.35 mmol) was dissolved in DCM (5 mL). Triethylamine (0.21 mL, 1.6 mmol), dimethylamine (0.54 mL, 1.1 mmol) and T3P (0.63 mL, 1.1 mmol) were sequentially added. The reaction mixture was stirred at RT overnight, then diluted with 1 M aq. Na₂CO₃ (5 mL). The aqueous layer was extracted with DCM (3×5 mL), the combined organic layers were dried over Na₂SO₄ and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel to yield CIS-2-(8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-1-yl)-N,N-dimethyl-acetamide (INT-978) (39 mg) as a white solid. [M+H]⁺ 359.2

Synthesis of INT-982: CIS-8-Dimethylamino-1-[(1-methyl-cyclobutyl)-methyl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one

Step 1: CIS-8-(dimethylamino)-3-(4-methoxybenzyl)-1-((1-methylcyclobutyl)methyl)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one

A solution of NaOH (2.85 g, 71.2 mmol) in DMSO (25 mL) was stirred at RT for 10 min. CIS-8-Dimethylamino-3-[(4-methoxyphenyl)-methyl]-8-phenyl-1,3-diazaspiro[4.5] decan-2-one (INT-975) (7.00 g, 17.8 mmol) was added and stirring was continued for 15 min. 1-(Bromo-methyl)-1-methyl-cyclobutane (8.7 g, 53.4 mmol) was added at 0° C. The reaction mixture was heated to 60° C. for 16 h. After cooling down to RT, water (100 mL) was added and the mixture was extracted with DCM (3×150 mL). The combined organic layers were washed with water (70 mL), brine (100 mL), dried over Na₂SO₄ and concentrated under reduced pressure. Purification of the residue by column chromatography on silica gel provided CIS-8-(dimethylamino)-3-(4-methoxybenzyl)-1-((1-methylcyclobutyl)methyl)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one (6.5 g) as a light yellow solid.

Step 2: CIS-8-Dimethylamino-1-[(1-methyl-cyclobutyl)-methyl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one

To the solution of CIS-8-Dimethylamino-1-[(1-methyl-cyclobutyl)-methyl]-8-phenyl-1,3-diazaspiro [4.5]decan-2-one (6.66 g, 14.0 mmol) in DCM (65 mL) was added TFA (65 mL) and the resulting mixture was stirred at RT for 16 h. The reaction mixture was concentrated under reduced pressure. The residue was taken up in DCM (100 mL) and water (60 mL) and basified with 2M aq. NaOH to pH 10. The organic layer was separated and washed with brine (40 mL), dried over MgSO₄, filtered and concentrated under reduced pressure. Crystallization of the residue from EtOAc provided CIS-8-Dimethylamino-1-[(1-methyl-cyclobutyl)-methyl]-8-phenyl-1,3-diazaspiro[4.5] decan-2-one (INT-982) (3.41 g) as an off-white solid. [M+H]⁺ 356.3

Synthesis of INT-984: CIS-1-(Cyclobutyl-methyl)-8-(ethyl-methyl-amino)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one

Step 1: CIS-8-(dimethylamino)-1-isobutyl-3-(4-methoxybenzyl)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one

In analogy to the method described for INT-951 step 1 CIS-8-Dimethylamino-3-[(4-methoxyphenyl)-methyl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one (INT-975) was converted into CIS-8-(dimethylamino)-1-isobutyl-3-(4-methoxybenzyl)-8-phenyl-1,3-diazaspiro [4.5]decan-2-one.

Step 2: CIS-1-(Cyclobutyl-methyl)-8-(ethyl-methyl-amino)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one

In analogy to the method described for INT-982 step 2 CIS-8-(dimethylamino)-1-isobutyl-3-(4-methoxybenzyl)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one was converted into CIS-1-(Cyclobutyl-methyl)-8-(ethyl-methyl-amino)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one (INT-984).

Synthesis of INT-986: CIS-1-(Cyclobutyl-methyl)-8-(ethyl-methyl-amino)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one

Step 1: CIS-3-benzyl-1-(cyclobutylmethyl)-8-(methylamino)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one

N-Iodosuccinimide (3.11 g, 13.92 mmol) was added to the solution of CIS-1-(Cyclobutyl-methyl)-8-dimethylamino-8-phenyl-3-[phenyl-methyl]-1,3-diazaspiro[4.5]decan-2-one (INT-950) (4 g, 9.28 mmol) in a mixture of acetonitrile and THF (1:1 v/v, 80 mL) and the resulting mixture was stirred at RT for 16 h. The reaction mixture was basified with 2N aq. NaOH to pH10 and the organic product was extracted with DCM (3×10 mL). The combined organic extracts were dried over anhydrous Na₂SO₄ and concentrated in vacuo. The residue was stirred vigorously with a mixture of 10 wt % aq. citric acid (5 mL) and DCM (10 mL) at RT for 10 min. The reaction mixture was basified with 5N aq. NaOH to pH10 and extracted with DCM (3×10 mL). The combined organic layer was dried over anhydrous Na₂SO₄ and concentrated in vacuo to give 3.5 g (crude) of CIS-3-benzyl-1-(cyclobutylmethyl)-8-(methylamino)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one as semi solid (TLC system: 10% MeOH in DCM; R_(f): 0.60.).

Step 2: CIS-3-benzyl-1-(cyclobutylmethyl)-8-(ethyl(methyl)amino)-8-phenyl-1,3-diazaspiro [4.5]decan-2-one

Sodium cyanoborohydride (1.56 g, 25.17 mmol, 3 equiv.) was added to the solution of CIS-3-benzyl-1-(cyclobutylmethyl)-8-(methylamino)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one (3.5 g, 8.39 mmol), acetaldehyde (738 mg, 16.78 mmol, 2 equiv.) and acetic acid (0.5 mL) in methanol (20 mL). The reaction mixture was stirred at RT for 3 h, then quenched with sat. aq. NaHCO₃ and the organic product was extracted with DCM (3×50 mL). The combined organic extracts were dried over anhydrous Na₂SO₄ and concentrated in vacuo. Purification of the residue by flash column chromatography on silica gel (230-400 mesh) (20-25% ethyl acetate in petroleum ether) yielded 2.3 g (62%) of CIS-3-benzyl-1-(cyclobutylmethyl)-8-(ethyl(methyl)amino)-8-phenyl-1,3-diazaspiro [4.5]decan-2-one as a solid. (TLC system: 50% EtOAc in Pet. Ether; R_(f): 0.65).

Step 3: CIS-1-(Cyclobutyl-methyl)-8-(ethyl-methyl-amino)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one (INT-986)

Sodium metal (1.18 g, 51.68 mmol, 10 equiv.) was added to liquid ammonia (25 mL) at -78° C. The resulting mixture was stirred for 10 min at −78° C. A solution of CIS-3-benzyl-1-(cyclobutylmethyl)-8-(ethyl(methyl)amino)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one (2.3 g, 5.16 mmol) in THF (25 mL) was added at −78° C. The reaction mixture was stirred for 15 min, then quenched with sat. aq. NH₄Cl, warmed to RT and stirred for 1 h. The organic product was extracted with DCM (3×50 mL). The combined organic layer was washed with water, brine and concentrated under reduced pressure to afford 1.30 g (72%) of CIS-1-(cyclobutylmethyl)-8-(ethyl(methyl)amino)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one (INT-986) as an off-white solid. (TLC system: 10% MeOH in DCM R_(f): 0.15.). [M+H]⁺ 356.3

Synthesis of INT-987: CIS-1-(Cyclobutyl-methyl)-8-dimethylamino-8-phenyl-1,3-diazaspiro[4.5]decan-2-one

In analogy to the method as described for INT-982 step 2 CIS-1-(Cyclobutyl-methyl)-8-dimethylamino-8-phenyl-3-[(4-methoxyphenyl)-methyl]-1,3-diazaspiro[4.5]decan-2-one (INT-952) was converted into CIS-1-(Cyclobutyl-methyl)-8-dimethylamino-8-phenyl-1,3-diazaspiro[4.5]decan-2-one (INT-987).

Synthesis of INT-988: CIS-8-(dimethylamino)-1-(2-(1-methoxycyclobutyl)ethyl)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one

Step 1: CIS-8-(dimethylamino)-1-[2-(1-methoxycyclobutyl)ethyl]-3-[(4-methoxyphenyl)methyl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one

Sodium hydroxide (78.06 mg, 4.0 equiv.) was suspended in DMSO (3.5 mL), stirred for 10 minutes, 8-(dimethylamino)-3-[(4-methoxyphenyl)methyl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one (INT-975) (192.0 mg, 1.0 equiv.) was added, the reaction mixture was stirred for 5 min followed by addition of 2-(1-methoxycyclobutyl)ethyl 4-methylbenzenesulfonate (416.2 mg, 3.0 equiv.) in DMSO (1.5 mL). The resulting mixture was stirred overnight at 50° C. The reaction mixture was quenched with water and extracted with DCM (3×20 mL). The combined organic phases were washed with brine, dried over Na₂SO₄ and concentrated under reduced pressure. The residue (283 mg yellow oil) was purified by column chromatography on silica gel (eluent DCM/EtOH 98/2 to 96/4) to give 8-(dimethylamino)-1-[2-(1-methoxycyclobutyl)ethyl]-3-[(4-methoxyphenyl)methyl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one 163 mg (66%).

Step 2: CIS-8-(dimethylamino)-1-(2-(1-methoxycyclobutyl)ethyl)-8-phenyl-1,3-diazaspiro[4.5] decan-2-one (INT-988)

In analogy to the method described for INT-982 step 2 CIS-8-(dimethylamino)-1-[2-(1-methoxycyclobutyl)ethyl]-3-[(4-methoxyphenyl)methyl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one was converted into CIS-8-(dimethylamino)-1-(2-(1-methoxycyclobutyl)ethyl)-8-phenyl-1,3-diazaspiro[4.5] decan-2-one (INT-988). Mass: m/z 386.3 (M+H)+.

Synthesis of INT-989: CIS-3-(2-chloropyrimidin-5-yl)-8-(dimethylamino)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one

CIS-8-(dimethylamino)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one (INT-976) (1250 mg, 4.6 mmol), 5-bromo-2-chloro-pyrimidine (1.5 equiv., 6.7 mmol, 1327 mg), Cs₂CO₃ (2 equiv., 9.15 mmol, 2980 mg), XantPhos (0.15 equiv., 0.69 mmol, 397 mg) and Pd₂(dba)₃ (0.05 equiv., 0.23 mmol, 209 mg) were dissolved in dry 1,4-dioxane (120 equiv., 549 mmol, 47 mL) under nitrogen atmosphere and stirred at 90° C. overnight. The reaction mixture was cooled down, diluted with water (50 mL), extracted with DCM (3×70 mL), the combined organic phases were dried over Na₂SO₄ and concentrated under reduced pressure. The residue (2.8 g) was suspended in 10 mL DCM and stirred for 10 min. The resulting precipitate was filtered off and washed with small amount of DCM to give 1213 mg of CIS-3-(2-chloropyrimidin-5-yl)-8-(dimethylamino)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one (INT-989) as a white solid. The mother liquor was concentrated under reduced pressure (1428 mg), suspended in 3 mL DCM, 3 mL pentane were slowly added and the mixture was stirred for 30 min. The precipitate was filtered off, washed with small amounts of pentane and DCM to give second portion of INT-989 (215 mg) as a light yellow solid. ¹H NMR (600 MHz, DMSO) δ 8.94 (s, 2H), 7.88 (s, 1H), 7.41-7.33 (m, 4H), 7.27 (tt, 1H), 3.65 (s, 2H), 2.49-2.32 (m, 2H), 1.98-1.88 (m, 2H), 1.96 (s, 6H), 1.87-1.73 (m, 2H), 1.53-1.47 (m, 2H). Mass: m/z 386.2 (M+H)⁺.

Synthesis of INT-991: lithium CIS-5-(8-(dimethylamino)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)pyrimidine-2-carboxylate

Methyl CIS-5-[8-(dimethylamino)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]pyrimidine-2-carboxylate (INT-990) (950 mg, 2.32 mmol) was suspended in a mixture of MeOH (140 equiv., 325 mmol, 13 mL) and THF (70 equiv., 162 mmol, 13 mL). Lithium hydroxide 2M aq. sol. (1.3 mL) was added. The reaction mixture was stirred 5 days at RT. Additional 1.3 mL of lithium hydroxide 2M aq. sol. were added and the reaction mixture was stirred for 2 h at RT. The solvents were removed under reduced pressure. The residue was suspended in EtOAc (10 mL) and stirred overnight. The precipitate was filtered off (1.07 g) and washed with DCM (3 mL), pentane and dried under reduced pressure. The resulting solid (960 mg) containing INT-990 and residual lithium salts was used directly in the next steps. Mass: m/z 394.2 (M−Li)⁻.

Synthesis of INT-1008: CIS-8-ethylamino-8-phenyl-1,3-diaza-spiro[4.5]decan-2-one

Step 1 and step 2: ethyl-(8-phenyl-1,4-dioxa-spiro[4.5]dec-8-yl)-amine hydrochloride (INT-1004)

A mixture of 1,4-dioxa-spiro[4.5]decan-8-one (25.0 g, 160.25 mmol, 1.0 eq.) and 2M solution of EtNH₂ in THF (200 ml, 2.5 eq. 400.64 mmol) in EtOH (30 ml) was stirred at RT for 48h. The reaction mixture was concentrated under argon atmosphere and the residue was diluted with ether (60 ml), and a freshly prepared PhLi solution was added [prepared by addition of 2.5M n-BuLi in THF (70.5 ml, 1.1 eq. 176.27 mmol) to a solution of bromobenzene (27.675 g, 1.1 eq. 176.275 mmol) in ether (100 ml) at −30° C. and stirred at RT for 1h). The reaction mixture was stirred at RT for 1.5h, quenched with saturated NH₄Cl solution (100 ml) at 0° C. and extracted with ethyl acetate (2×750 ml). The combined organic layer was washed with water (3×350 ml), brine (300 ml), dried over Na₂SO₄ and concentrated under reduced pressure. The resulting residue was dissolved in ethyl methyl ketone (100 ml) and trimethylsilyl chloride (37.5 ml) was added at 0° C. The resulting mixture was stirred at RT for 16h. The precipitated solid was filtered off and washed with acetone followed by THF to get ethyl-(8-phenyl-1,4-dioxa-spiro[4.5]dec-8-yl)-amine hydrochloride as an off white solid. This reaction was done in 2 batches of 25 g scale and the yield is given for 2 combined batches. Yield: 18% (17.1 g, 57.575 mmol). LCMS: m/z 262.2 (M+H)⁺.

Step 3: 4-ethylamino-4-phenyl-cyclohexanone (INT-1005)

To a solution of ethyl-(8-phenyl-1,4-dioxa-spiro[4.5]dec-8-yl)-amine hydrochloride (10.1 g, 34.0 mmol, 1 eq.) in water (37.5 ml) was added conc. aq. HCl (62.5 ml) at 0° C. and the resulting mixture was stirred at RT for 16 h. The reaction mixture was basified with aq. NaOH (pH 14) at 0° C. and extracted with DCM (2×750 ml). Organic layer was washed with water (400 ml), brine (400 ml), dried over Na₂SO₄ and concentrated under reduced pressure to yield 4-ethylamino-4-phenyl-cyclohexanone which was used in the next step without further purification. This reaction was carried out in another batch of 15.1 g scale and the yield is given for 2 combined batches. Yield: 92% (17.0 g, 78.34 mmol).

Step 4: cis and trans mixture of 8-ethylamino-8-phenyl-1,3-diaza-spiro[4.5]decane-2,4-dione (INT-1006 and INT-1007)

To a solution of 4-ethylamino-4-phenyl-cyclohexanone (17 g, 78.341 mmol, 1.0 eq.) in EtOH (250 ml) and water (200 ml) was added (NH₄)₂CO₃ (18.8 g, 195.85 mmol, 2.5 eq.) and the reaction mixture was stirred at RT for 15 min. KCN (5.09 g, 78.341 mmol, 1.0 eq.) was added and stirring was continued at 60° C. for 18 h. The reaction mixture was cooled down to RT. The precipitated solid was filtered off, washed with water (250 ml), EtOH (300 ml), hexane (200 ml) and dried under reduced pressure to yield cis and trans mixture of 8-ethylamino-8-phenyl-1,3-diaza-spiro[4.5]decane-2,4-dione (13.0 g, 45.29 mmol, 58%) as a white solid. Yield: 58% (13 g, 45.296 mmol). LC-MS: m/z [M+1]⁺=288.2.

Step 5: CIS-8-ethylamino-8-phenyl-1,3-diaza-spiro[4.5]decane-2,4-dione (INT-1006)

To a solution of cis and trans mixture of 8-ethylamino-8-phenyl-1,3-diaza-spiro[4.5]decane-2,4-dione (12 g) in MeOH-DCM (1:1, 960 ml) was added a solution of L-tartaric acid in MeOH (25 ml) and the resulting mixture stirred at RT for 2 h and then kept in refrigerator for 16 h. The precipitated solid was filtered off and washed with MeOH-DCM (1:5, 50 ml) to get tartrate salt of 8-ethylamino-8-phenyl-1,3-diaza-spiro[4.5]decane-2,4-dione (7.5 g) as a white solid. To this solid sat. aq. NaHCO₃ was added (pH8) and the resulting mixture was extracted with 25% MeOH-DCM (2×800 ml). Combined organic layer was washed with water (300 ml), brine (300 ml), dried over anhydrous Na₂SO₄ and concentrated under reduced pressure. The residue was triturated with 20% DCM-hexane and the resulting solid was dried under reduced pressure to afford CIS-8-ethylamino-8-phenyl-1,3-diaza-spiro[4.5]decane-2,4-dione as white solid. This step was done in 2 batches (12 g & 2.4 g) and the yield is given for 2 combined batches. Yield: 31.2% (5.0 g, 17.421 mmol). LC-MS: m/z [M+1]=288.0.

Step 6: CIS-8-ethylamino-8-phenyl-1,3-diaza-spiro[4.5]decan-2-one (INT-1008)

To a slurry of LiAlH₄ (793 mg, 20.91 mmol, 3.0 eq.) in THF (15 ml) was added a suspension of CIS-8-ethylamino-8-phenyl-1,3-diaza-spiro[4.5]decane-2,4-dione (2.0 g, 6.97 mmol, 1.0 eq.) in THF (60 ml) at 0° C. and the reaction mixture was heated to 65° C. for 16 h. The reaction mixture was cooled to 0° C., quenched with sat. aq. Na₂SO₄ (20 ml), stirred at RT for 1h and filtered through celite pad. The residue was washed with 15% MeOH-DCM (500 ml). The combined filtrate was dried over anhydrous Na₂SO₄ and concentrated under reduced pressure to give crude product which was triturated with 15% DCM-Hexane to afford CIS-8-ethylamino-8-phenyl-1,3-diaza-spiro[4.5]decan-2-one (INT-1008) (1.6 g, 5.86 mmol, 84%) as a white solid. Yield: 84% (1.6 g, 5.86 mmol). LC-MS: m/z [M+1]⁺=274.2.

Synthesis of INT-1026: CIS-8-(methyl((tetrahydrofuran-3-yl)methyl)amino)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one

Step 1:2-methyl-N-(1,4-dioxaspiro[4.5]decan-8-ylidene)propane-2-sulfinamide

Titanium ethoxide (58.45 g, 256.4 mmol) was added to a solution of 1,4-dioxaspiro[4.5]decan-8-one (20 g, 128.20 mmol) and 2-methylpropane-2-sulfinamide (15.51 g, 128.20 mmol) in THF (200 mL) at RT and the reaction mixture was stirred at RT for 18h. The reaction mixture was cooled to 0° C. and quenched by dropwise addition of sat. aq. NaHCO₃ (500 mL) over a period of 30 min. The organic product was extracted with EtOAc (3×100 mL). The combined organic extracts were dried over anhydrous Na₂SO₄ and concentrated in vacuo to afford 10 g (crude) of 2-methyl-N-(1,4-dioxaspiro[4.5]decan-8-ylidene)propane-2-sulfinamide as a white solid (TLC system: 30% Ethyl acetate in hexane; Rf: 0.30).

Step 2: 2-methyl-N-(8-phenyl-1,4-dioxaspiro[4.5]decan-8-yl)propane-2-sulfinamide

Phenylmagnesium bromide (1M in THF, 116 mL, 116 mmol) was added dropwise to a solution of 2-methyl-N-(1,4-dioxaspiro[4.5]decan-8-ylidene)propane-2-sulfinamide (10 g, 38.61 mmol) in THF (500 mL) at −10° C. under argon atmosphere. The reaction mixture was stirred for 2h at −10° C. to 0° C. The reaction completion was monitored by TLC. The reaction mixture was quenched with sat. aq. NH₄Cl (50 mL) at 0° C. and the organic product was extracted with EtOAc (3×100 mL). The combined organic extracts were dried over anhydrous Na₂SO₄ and concentrated in vacuo. The residue was purified by column chromatography (silica gel 230-400 mesh; 40-60% ethyl acetate in hexane) to yield 6.0 g (46%) of 2-methyl-N-(8-phenyl-1,4-dioxaspiro[4.5]decan-8-yl)propane-2-sulfinamide as a liquid (TLC system: 70% Ethyl acetate in hexane; Rf: 0.30).

Step 3: 8-phenyl-1,4-dioxaspiro[4.5]decan-8-amine hydrochloride

2N solution of HCl in diethyl ether (17.80 mL, 35.60 mmol) was added to a solution of 2-methyl-N-(8-phenyl-1,4-dioxaspiro[4.5]decan-8-yl)propane-2-sulfinamide (6.0 g, 17.80 mmol) in DCM (60 mL) at 0° C. The reaction mixture was stirred at RT for 2 h. The reaction mixture was concentrated in vacuo. The residue was washed with diethyl ether to yield 3 g (crude) of 8-phenyl-1,4-dioxaspiro[4.5]decan-8-amine hydrochloride as a brown solid (TLC system: 5% MeOH in DCM; Rf: 0.10).

Step 4: 8-phenyl-N-((tetrahydrofuran-3-yl)methyl)-1,4-dioxaspiro[4.5]decan-8-amine

Sodium cyanoborohydride (2.17 g, 33.45 mmol) was added to a solution of 8-phenyl-1,4-dioxaspiro[4.5]decan-8-amine hydrochloride (3.0 g, 11.15 mmol) and tetrahydrofuran-3-carbaldehyde (4.46 mL, 22.30 mmol) and acetic acid (0.05 mL) in methanol (30 mL) at 0° C. The reaction mixture was stirred at RT for 16h. The reaction mixture was concentrated in vacuo at 30° C. and to the residue sat. aq. NaHCO₃ was added. The organic product was extracted with DCM (3×30 mL). The combined organic extracts were dried over anhydrous Na₂SO₄ and solvent was concentrated under reduced pressure to get 3 g (crude) of 8-phenyl-N-((tetrahydrofuran-3-yl)methyl)-1,4-dioxaspiro[4.5]decan-8-amine as a semi-solid (TLC system: 10% MeOH in DCM; Rf: 0.22).

Step 5: N-methyl-8-phenyl-N-((tetrahydrofuran-3-yl)methyl)-1,4-dioxaspiro[4.5]decan-8-amine)

Sodium cyanoborohydride (1.76 g, 28.39 mmol) was added to a solution of 8-phenyl-N-((tetrahydrofuran-3-yl)methyl)-1,4-dioxaspiro[4.5]decan-8-amine (3.0 g, 9.46 mmol), 37% formaldehyde in water (7.70 mL, 94.60 mmol) and acetic acid (0.05 mL) in methanol (30 mL) at 0° C. The reaction mixture was stirred at RT for 16 h. The reaction mixture was concentrated in vacuo and to the residue sat. aq. NaHCO₃ was added. The organic product was extracted with DCM (3×30 mL). The combined organic extracts were dried over anhydrous Na₂SO₄ and solvent was concentrated under reduced pressure. The resulting residue was purified by column chromatography (silica gel 230-400 mesh; 5-6% MeOH in DCM) to yield 2.50 g (83%) of N-methyl-8-phenyl-N-((tetrahydrofuran-3-yl)methyl)-1,4-dioxaspiro[4.5]decan-8-amine as a semi solid (TLC system: 10% MeOH in DCM; R_(f): 0.25).

Step 6: 4-(methyl((tetrahydrofuran-3-yl)methyl)amino)-4-phenylcyclohexanone

5% sulfuric acid in water (25 mL) was added to N-methyl-8-phenyl-N-((tetrahydrofuran-3-yl)methyl)-1,4-dioxaspiro[4.5]decan-8-amine (2.50 g, 7.55 mmol) at 0° C. and the resulting mixture was stirred at RT for 24 h. The reaction mixture was quenched with sat. aq. NaHCO₃ and the organic product was extracted with DCM (2×50 mL). The combined organic layers were dried over anhydrous Na₂SO₄ and concentrated in vacuo to afford 2.0 g (crude) of 4-(methyl((tetrahydrofuran-3-yl)methyl)amino)-4-phenylcyclohexanone as a thick liquid (TLC system: 10% MeOH in DCM, Rf: 0.20).

Step 7: 8-(methyl((tetrahydrofuran-3-yl)methyl)amino)-8-phenyl-1,3-diazaspiro[4.5]decane-2,4-dione

4-(methyl((tetrahydrofuran-3-yl)methyl)amino)-4-phenylcyclohexanone (1.50 g, 5.22 mmol) was suspended in 30 mL of EtOH:H₂O (1:1 v/v) at RT under argon atmosphere. (NH₄)₂CO₃ (1.9 g, 13.05 mmol) and KCN (0.34 g, 5.22 mmol) were added. The reaction mixture was heated to 70° C. for 16 h. The reaction mixture was diluted with ice-water and the organic product was extracted with DCM (2×50 mL). The combined organic layer was dried over anhydrous Na₂SO₄ and concentrated in vacuo to give 1.0 g (crude) of 8-(methyl((tetrahydrofuran-3-yl)methyl)amino)-8-phenyl-1,3-diazaspiro[4.5]decane-2,4-dione as a solid (TLC system: 70% Ethyl acetate in hexane; Rf: 0.18).

Step 8: CIS-8-(methyl((tetrahydrofuran-3-yl)methyl)amino)-8-phenyl-1,3-diazaspiro[4.5]decane-2,4-dione

Diastereomeric mixture of 8-(methyl((tetrahydrofuran-3-yl)methyl)amino)-8-phenyl-1,3-diazaspiro[4.5]decane-2,4-dione (1.0 g) was separated by reverse phase preparative HPLC to afford 400 mg of isomer 1 (CIS-8-(methyl((tetrahydrofuran-3-yl)methyl)amino)-8-phenyl-1,3-diazaspiro[4.5]decane-2,4-dione) and 60 mg of isomer 2 (TRANS-8-(methyl((tetrahydrofuran-3-yl)methyl)amino)-8-phenyl-1,3-diazaspiro[4.5]decane-2,4-dione) and 300 mg of mixture of both isomers. Reverse phase preparative HPLC conditions: mobile phase: 10 mM ammonium bicarbonate in H₂O/acetonitrile, column: X-BRIDGE-C18 (150*30), 5 μm, gradient (T/B %): 0/35, 8/55, 8.1/98, 10/98, 10.1/35, 13/35, flow rate: 25 ml/min, diluent: mobile phase+THF.

Step 9: CIS-8-(methyl((tetrahydrofuran-3-yl)methyl)amino)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one (INT-1026)

LiAlH₄ (1M in THF) (4.48 mL, 4.48 mmol) was added to a solution of CIS-8-(methyl((tetrahydrofuran-3-yl)methyl)amino)-8-phenyl-1,3-diazaspiro[4.5]decane-2,4-dione (isomer-1) (0.4 g, 1.12 mmol) in THF:Et₂O (2:1 v/v, 15 mL) at 0° C. under argon atmosphere. The reaction mixture was stirred at 65° C. for 16 h. The mixture was cooled to 0° C., quenched with sat. aq. Na₂SO₄ (1000 mL) and filtered through celite pad. The filtrate was dried over anhydrous Na₂SO₄ and concentrated in vacuo. The residue was purified by column chromatography (silica gel 230-400 mesh; 5-6% MeOH in DCM) to yield 0.3 g (78%) of CIS-8-(methyl((tetrahydrofuran-3-yl)methyl)amino)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one (INT-1026) as an off white solid. (TLC system: 10% MeOH in DCM, Rf: 0.2). LC-MS: m/z [M+1]⁺=344.2.

Synthesis of INT-1031: CIS-1-(Cyclobutyl-methyl)-8-dimethylamino-8-(3-fluorophenyl)-1,3-diazaspiro[4.5]decan-2-one

Step 1: CIS-1-(Cyclobutyl-methyl)-8-dimethylamino-8-(3-fluorophenyl)-3-[(4-methoxyphenyl)-methyl]-1,3-diazaspiro[4.5]decan-2-one

In analogy to the method described for INT-952 CIS-8-dimethylamino-8-(3-fluorophenyl)-3-[(4-methoxyphenyl)-methyl]-1,3-diazaspiro[4.5]decan-2-one (INT-974) was converted into CIS-1-(cyclobutyl-methyl)-8-dimethylamino-8-(3-fluorophenyl)-3-[(4-methoxyphenyl)-methyl]-1,3-diazaspiro[4.5]decan-2-one.

Step 2: CIS-1-(Cyclobutyl-methyl)-8-dimethylamino-8-(3-fluorophenyl)-1,3-diazaspiro[4.5]decan-2-one

In analogy to the method described for INT-982 step 2 1-(cyclobutyl-methyl)-8-dimethylamino-8-(3-fluorophenyl)-3-[(4-methoxyphenyl)-methyl]-1,3-diazaspiro[4.5]decan-2-one was converted into 1-(cyclobutyl-methyl)-8-dimethylamino-8-(3-fluorophenyl)-1,3-diazaspiro[4.5]decan-2-one (INT-1031).

Synthesis of INT-1037: 8-(dimethylamino)-2-oxo-1,3-diazaspiro[4.5]decane-8-carbonitrile

Step 1: 9,12-dioxa-2,4-diazadispiro[4.2.4{circumflex over ( )}{8}.2{circumflex over ( )}{5}]tetradecan-3-one

Lithiumaluminiumhydride (2.2 equiv., 292 mmol) was suspended in THF (400 mL) and the suspension was cooled to 0° C. 8-(Dimethylamino)-8-(m-tolyl)-1,3-diazaspiro[4.5]decan-2-one (B, 75 mg, 0,261 mmol) (step 1 of INT-965) was added portionwise at 0° C. The reaction mixture was stirred 1.5 h at 0° C., then overnight at RT and then 2 h at 40° C. The reaction mixture was cooled down to 0° C., quenched carefully with sat. aq. Na₂SO₄, EtOAc (400 mL) was added and the resulting mixture was stirred for 2 h and then left without stirring for 2h at RT. The precipitate was filtered off and washed with EtOAc and MeOH. The resulting solid residue was suspended in methanol and stirred at RT overnight. The precipitate was filtered off and disposed. The filtrate was concentrated under reduced pressure, the residue was suspended thoroughly in water (50 mL) at 40° C., the precipitate was filtered off and dried under reduced pressure to yield 9,12-dioxa-2,4-diazadispiro[4.2.4{circumflex over ( )}{8}.2{circumflex over ( )}{5}]tetradecan-3-one (11.4 g, 41%). Mass: m/z 213.2 (M+H)⁺.

Step 2: 1,3-diazaspiro[4.5]decane-2,8-dione

In analogy to the method described for INT-1003 step 3 9,12-dioxa-2,4-diazadispiro[4.2.4{circumflex over ( )}{8}.2{circumflex over ( )}{5}]tetradecan-3-one was treated with conc. aq. HCl to be converted into 1,3-diazaspiro[4.5]decane-2,8-dione. Mass: m/z 169.1 (M+H)⁺.

Step 3: 8-(dimethylamino)-2-oxo-1,3-diazaspiro[4.5]decane-8-carbonitrile (INT-1037)

In analogy to the method described for INT-965 step 1 1,3-diazaspiro[4.5]decane-2,8-dione was treated with dimethyl amine and potassium cyanide to be converted into 8-(dimethylamino)-2-oxo-1,3-diazaspiro[4.5]decane-8-carbonitrile (INT-1037). Mass: m/z 223.2 (M+H)⁺.

Synthesis of INT-1038: CIS-8-(dimethylamino)-8-(m-tolyl)-1,3-diazaspiro[4.5]decan-2-one

To the suspension of 8-(dimethylamino)-2-oxo-1,3-diazaspiro[4.5]decane-8-carbonitrile (200 mg, 0.90 mmol) in THF (4 mL) at RT was added dropwise IM bromo(m-tolyl)magnesium in THF (4 equiv., 3.6 mmol, 3.6 mL) and the reaction mixture was stirred for 1 h at RT. Additional portion of IM bromo(m-tolyl)magnesium in THF (1 equiv., 0.8 mL) was added. The reaction mixture was stirred at RT overnight, then quenched with methanol/water. Solid NH₄Cl and DCM were added to the resulting mixture and the precipitate was filtered off. The organic phase of the filtrate was separated and the aqueous phase was extracted with DCM (3×). The combined organic phases were dried over anhydr. Na₂SO₄ and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel (DCM/MeOH, 100/0 to 65/35) to yield CIS-8-(dimethylamino)-8-(m-tolyl)-1,3-diazaspiro[4.5]decan-2-one (INT-1038) (81 mg, 31%). Mass: m/z 288.2 (M+H)⁺.

Synthesis of INT-1059: TRANS-8-(dimethylamino)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one

Step 1: TRANS-8-(dimethylamino)-8-phenyl-1,3-diazaspiro[4.5]decane-2,4-dione

To a stirred solution of 4-dimethylamino-4-phenyl-cyclohexanone (250.0 g, 1.15 mol, 1.0 eq.) in EtOH (2.5 L) and water (2.1 L) was added (NH₄)₂CO₃ (276.2 g, 2.87 mol, 2.5 eq.) and the reaction mixture was stirred at RT for 15 min. KCN (74.92 g, 1.15 mol, 1.0 eq.) was added. The reaction mixture was stirred at 60° C. for 18h and then filtered in hot condition to get white solid which was washed with water (2.5 L), ethanol (1 L) and hexane (2.5 L). The resulting solid was dried under reduced pressure to get CIS-8-dimethylamino-8-phenyl-1,3-diaza-spiro[4.5]decane-2,4-dione (223 g, 0.776 mol, 65%) as a white solid. The filtrate was collected from multiple batches (450 g) which contained a mixture of cis and trans isomers. The filtrate was concentrated under reduced pressure and solid obtained was filtered and washed with water (1 L) and hexane (1 L). Solid material was dried under reduced pressure to get 100 g of a mixture of cis and trans (major) isomers. Crude material was partially dissolved in hot MeOH (600 mL) and cooled to RT, filtered through sintered funnel, washed with MeOH (200 mL) followed by ether (150 mL) and dried to get TRANS-8-dimethylamino-8-phenyl-1,3-diaza-spiro[4.5]decane-2,4-dione (50 g, 0.174 mmol, 9-10%).

Step 2: TRANS-8-(dimethylamino)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one (INT-1059)

In analogy to the method described for INT-976 step 2 TRANS-8-dimethylamino-8-phenyl-1,3-diaza-spiro[4.5]decane-2,4-dione was treated with LiAlH₄ to be converted into TRANS-8-(dimethylamino)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one (INT-1059). Mass: m/z 274.2 (M+H)⁺.

Synthesis of INT-1068 and INT-1069: CIS- and TRANS-8-(dimethylamino)-8-phenyl-1-(2,2,2-trifluoroethyl)-1,3-diazaspiro[4.5]decan-2-one

Step 1: 1-amino-4-dimethylamino-4-phenyl-cyclohexanecarbonitrile

To a stirred solution of 4-dimethylamino-4-phenyl-cyclohexanone (50 g, 230.096 mmol) in MeOH (400 mL) was added NH₄Cl(24.6 g, 460.8 mmol) followed by NH₄OH (400 mL) at RT and the reaction mixture was stirred for 15 min. NaCN (22.5 g, 460.83 mmol) was added and the resulting mixture was stirred for 16 h at RT. The reaction mixture was extracted with DCM (3×750 mL). Combined organic layer was washed with water (750 mL), brine (750 mL), dried over Na₂SO₄ and concentrated under reduced pressure. The residue was triturated with DCM/hexane to get crude 1-amino-4-dimethylamino-4-phenyl-cyclohexanecarbonitrile (50 g, 90%) as an off white solid which was used in next step without further purification. LC-MS: m/z [M+H]⁺=244.2 (MW calc. 244.09).

Step 2: N-(1-cyano-4-dimethylamino-4-phenyl-cyclohexyl)-2,2,2-trifluoroacetamide

To a solution of 1-amino-4-dimethylamino-4-phenyl-cyclohexanecarbonitrile (5.0 g, 20.57 mmol, 1.0 eq.) in THF (100 ml) were added DIPEA (10.72 ml, 61.71 mmol, 3.0 eq), trifluoroacetic acid (1.89 ml, 24.69 mmol, 1.2 eq) and T3P (18.2 ml, 30.85 mmol, 1.5 eq) at 0° C. The reaction mixture was stirred at RT for 16h, then diluted with water (100 ml) and extracted with 10% MeOH in DCM (2×250 mL). Combined organic layer was washed with brine (100 mL), dried over Na₂SO₄ and concentrated under reduced pressure to get crude N-(1-cyano-4-dimethylamino-4-phenyl-cyclohexyl)-2,2,2-trifluoroacetamide as a light yellow sticky material which was used in the next step without further purification. LC-MS: m/z [M+1]=339.9 (MW calc. 339.36).

Step 3: 1-aminomethyl-N′,N′-dimethyl-4-phenyl-N-(2,2,2-trifluoroethyl)cyclohexane-1,4-diamine

To suspension of LiAlH₄ (4.03 g, 106.19 mmol, 6.0 eq.) in dry THF (40 mL) was added N-(1-cyano-4-dimethylamino-4-phenyl-cyclohexyl)-2,2,2-trifluoro-acetamide (6.0 g, 17.69 mmol, 1.0 eq.) in dry THF (100 mL) dropwise at 0° C. The reaction mixture was stirred at RT for 16 h, then quenched with sat. aq. Na₂SO₄ at 0° C., excess THF was added and the resulting mixture was stirred at RT for 2 h. The resulting suspension was filtered through celite and the filter cake was washed with 10% MeOH in DCM (150 mL). Combined filtrate was concentrated under reduced pressure to yield crude 1-aminomethyl-N′,N′-dimethyl-4-phenyl-N-(2,2,2-trifluoro-ethyl)-cyclohexane-1,4-diamine (4.2 g, crude) as a light yellow sticky material which was directly used in the next step without further purification. LC-MS: m/z [M+1]*=330.0 (MW calc. 329.40).

Step 4: CIS- and TRANS-8-dimethylamino-8-phenyl-1-(2,2,2-trifluoro-ethyl)-1,3-diaza-spiro[4.5]decan-2-one (INT-1068 and INT-1069)

To a solution of 1-aminomethyl-N′,N′-dimethyl-4-phenyl-N-(2,2,2-trifluoro-ethyl)-cyclohexane-1,4-diamine (4.2 g, 12.76 mmol, 1.0 eq.) in toluene (60 ml) was added KOH (4.29 g, 76.56 mmol, 6.0 eq.) in water (120 ml) at 0° C. followed by addition of COCl₂ (15.6 ml, 44.66 mmol, 3.5 eq., 20% in toluene) at 0° C. and stirred at RT for 16 h. Reaction mixture was basified with sat NaHCO₃ solution and extracted with DCM (2×200 ml). Combined organic layer was dried over Na₂SO₄ and concentrated under reduced pressure to get crude product which was purified by prep HPLC to get CIS-8-dimethylamino-8-phenyl-1-(2,2,2-trifluoro-ethyl)-1,3-diaza-spiro[4.5]decan-2-one (INT-1068) (1.5 g) (major isomer, polar spot on TLC) and TRANS-8-dimethylamino-8-phenyl-1-(2,2,2-trifluoro-ethyl)-1,3-diaza-spiro[4.5]decan-2-one (INT-1069) as minor isomer (non-polar spot on TLC) (120 mg, 92.93% by HPLC) as off-white solids. CIS-isomer: LC-MS: m/z [M+1]⁺=356.2 (MW calc.=355.40). HPLC: 98.53%, Column: Xbridge C-18 (100×4.6), 5p, Diluent: MeOH, Mobile phase: A) 0.05% TFA in water; B) ACN flow rate: 1 ml/min, Rt=5.17 min. ¹HNMR (DMSO-d₆, 400 MHz), δ (ppm)=7.43-7.27 (m, 5H), 6.84 (s, 1H), 3.30-3.25 (m, 4H), 2.66-2.63 (d, 2H, J=12.72 Hz), 1.89 (s, 6H), 1.58-1.51 (m, 2H), 1.46-1.43 (m, 2H), 1.33-1.23 (m, 2H).

For further intermediates the synthesis in analogy to previously described methods is given in the following table. The syntheses of the building blocks and intermediates have either been described previously within this application or can be performed in analogy to the herein described methods or by methods known to the person, skilled in the art. Such a person will also know which building blocks and intermediates need to be chosen for synthesis of each exemplary compound.

Inter- in analogy to m/z mediate Chemical Name Chemical Structure method [M + H]⁺ INT-601 CIS-5-(-8- (dimethylamino)- 8-(3-fluorophenyl)-2- oxo-1,3-diazaspiro[4.5] decan-3-yl)pyrimidine- 2-carbonitrile

INT-600 395.1 INT-794 CIS-3-(3,4- dimethoxybenzyl)-8- (dimethylamino)-8- phenyl-1,3- diazaspiro [4.5]decan-2-one

INT-975 424.3 INT-796 CIS-8-Dimethylamino-3- [(4-methoxyphenyl)- methyl]-8-(3-methoxy- propyl)-1,3-diazaspiro [4.5]decan-2-one

INT-974 390.3 INT-797 CIS-8-(Ethyl- methyl-amino)- 8-phenyl-1,3- diazaspiro[4.5] decan-2-one

INT-976 288.2 INT-949 CIS-8-Dimethylamino- 1-ethyl-8-phenyl-1,3- diazaspiro[4.5] decan-2-one

INT-984 302.2 INT-950 CIS-1-(Cyclobutyl- methyl)-8- dimethylamino-8- phenyl-3-[phenyl- methyl]-1,3- diazaspiro[4.5] decan-2-one

INT-952 432.3 INT-954 4-Dimethylamino-4- (5-methyl-thiophen- 2-yl)-cyclohexan-1-one

INT-965 238.1 INT-955 4-Dimethylamino-4- thiophen-2-yl- cyclohexan-1-one

INT-965 224.1 INT-956 1-(1-Methyl-1H- pyrazol-3-yl)-4-oxo- cyclohexane-1- carbonitrile

INT-958 204.1 INT-957 4-Oxo-1-pyrazin-2-yl- cyclohexane-1- carbonitrile

INT-958 202.1 INT-959 4-Dimethylamino-4-(1- methyl-1H-pyrazol-3-yl)- cyclohexan-1-one

INT-961 222.2 INT-960 4-Dimethylamino-4- pyrazin-2-yl-cyclohexan- 1-one

INT-961 220.1 INT-962 4-Dimethylamino-4- (3-methoxyphenyl)- cyclohexan-1-one

INT-965 248.2 INT-963 CIS-3-Benzyl-8- dimethylamino- 8-phenyl-1,3- diazaspiro[4.5] decan-2-one

INT-975 364.2 INT-964 4-(Ethyl-methyl-amino)- 4-phenyl-cyclohexan-1- one

INT-965 232.2 INT-967 CIS-8-Dimethylamino- 8-[4- (methoxymethyloxy)- phenyl]-3-[(4- methoxyphenyl)- methyl]-1,3- diazaspiro[4.5] decan-2-one

INT-974 454.3 INT-968 CIS-8-Dimethylamino- 8-[3- (methoxymethyloxy)- phenyl]-3-[(4- methoxyphenyl)- methyl]-1,3- diazaspiro[4.5]decan- 2-one

INT-974 454.3 INT-969 CIS-1-(Cyclobutyl- methyl)- 8-dimethylamino-8- (4-hydroxyphenyl)-3- [(4-methoxyphenyl)- methyl]-1,3-diazaspiro [4.5]decan-2-one

INT-971 478.3 INT-970 CIS-8-Dimethylamino- 8-(4-methoxyphenyl)-3- [(4-methoxyphenyl)- methyl]-1,3- diazaspiro[4.5] decan-2-one

SC_2017 424.3 INT-972 CIS-8- Dimethylamino-8- (3-methoxyphenyl)-3- [(4-methoxyphenyl)- methyl]-1,3- diazaspiro[4.5]decan- 2-one

SC_2017 424.3 INT-973 CIS-8- Dimethylamino-8- (4-fluorophenyl)-3-[(4- methoxyphenyl)- methyl]-1,3-diazaspiro [4.5]decan-2-one

INT-974 412.2 INT-979 CIS-8-Dimethylamino- 1-(3-methoxy-propyl)-8- phenyl-1,3-diazaspiro [4.5]decan-2-one

INT-984 346.2 INT-980 CIS-8-Dimethylamino-1- (2-methoxy-ethyl)-8- phenyl-1,3-diazaspiro [4.5]decan-2-one

INT-984 332.2 INT-981 CIS-8-Dimethylamino-8- phenyl-1-propyl-1,3- diazaspiro[4.5]decan- 2-one

INT-984 316.2 INT-983 CIS-1-(Cyclopropyl- methyl)-8- dimethylamino-8- phenyl-1,3-diazaspiro [4.5]decan-2-one

INT-984 328.2 INT-985 CIS-1-(Cyclobutyl- methyl)- 8-(methyl-propyl- amino)-8-phenyl-1,3- diazaspiro [4.5]decan-2-one

INT-986 370.3 INT-990 methyl CIS-5-(8- (dimethylamino)-2-oxo- 8-phenyl-1,3-diazaspiro [4.5]decan- 3-yl)pyrimidine- 2-carboxylate

INT-989 410.2 INT-992 CIS-3-(2-chloro-4- methylpyrimidin-5-yl)-8- (dimethylamino)- 8-phenyl-1,3- diazaspiro[4.5]decan- 2-one

INT-989 400.2 INT-993 4-benzyl-4- (dimethylamino) cyclochexanone

INT-965 232.3 INT-994 CIS-8-benzyl-8- (dimethylamino)-1,3- diazaspiro[4.5]decan- 2-one

INT-976 288.2 INT-995 TRANS-8-benzyl-8- (dimethylamino)-1,3- diazaspiro[4.5]decan- 2-one

INT-976 288.2 INT-997 CIS-8-(dimethylamino)- 8-(thiophen-2-yl)-1,3- diazaspiro[4.5]decan- 2-one

INT-976 280.1 INT-998 TRANS-8- (dimethylamino)- 8-(thiophen-2-yl)- 1,3-diazaspiro[4.5] decan-2-one

INT-976 280.1 INT-999 4-(dimethylamino)- 4-(1-methyl-1H- benzo[d]imidazol-2-yl) cyclohexanone

INT-965 272.2 INT-1000 CIS-8-(dimethylamino)- 8-(1-methyl-1H- benzo[d]imidazol-2-yl)- 1,3-diazaspiro [4.5]decan-2-one

INT-976 328.2 INT-1001 TRANS-8- (dimethylamino)- 8-(1-methyl-1H- benzo[d]imidazol- 2-yl)-1,3- diazaspiro[4.5] decan-2-one

INT-976 328.2 INT-1002 CIS-3-(2- chloropyrimidin- 4-yl)-8- (dimethylamino)-8- phenyl-1,3- diazaspiro[4.5] decan-2-one

INT-989 386.9 INT-1009 TRANS-8-ethylamino- 8-phenyl-1,3-diaza- spiro[4.5]decan-2-one

INT-1008 274.2 INT-1024 CIS-8-(dimethylamino)- 8-(3-fluorophenyl)-1,3- diazaspiro[4.5] decan-2-one

INT-977 (step 2) 292.2 INT-1025 CIS-8-(dimethylamino)- 8-(4-fluorophenyl)-1,3- diazaspiro[4.5] decan-2-one

INT-974, INT-977 (step 2) 292.2 INT-1027 CIS-3-(2- chloropyrimidin-5-yl)- 8-(dimethylamino)-8- (thiophen- 2-yl)-1,3- diazaspiro[4.5] decan-2-one

INT-989 392.1 INT-1039 CIS-8-(dimethylamino)- 8-(3- (trifluoromethoxy) phenyl)-1,3- diazaspiro[4.5] decan-2-one

INT-1038 358.2 INT-1040 (CIS)-8- (dimethylamino)-8-(3- (trifluoromethyl) phenyl)- 1,3-diazaspiro [4.5]decan-2-one

INT-1038 342.2 INT-1041 (CIS)-8- (dimethylamino)- 8-(3-methoxyphenyl)- 1,3-diazaspiro[4.5] decan-2-one

INT-1038 304.2 INT-1042 (CIS)-8-(5- chlorothiophen-2-yl)-8- (dimethylamino)-1,3- diazaspiro[4.5] decan-2-one

INT-1038 314.1 INT-1043 (CIS)-8- (dimethylamino)- 8-(3-fluoro-5- methylphenyl)- 1,3-diazaspiro [4.5]decan-2-one

INT-1038 306.2 INT-1044 (CIS)-8-(3-chlorophenyl)- 8-(dimethylamino)-1,3- diazaspiro[4.5] decan-2-one

INT-1038 308.2 INT-1045 (CIS)-3-(5-chloro- 3-fluoropyridin-2-yl)-8- (dimethylamino)- 8-phenyl-1,3- diazaspiro[4.5] decan-2-one

INT-989 403.2 INT-1047 (CIS)-8-(methyl(oxetan- 3-ylmethyl)amino)-8- phenyl-1,3-diazaspiro [4.5]decan-2-one

INT-1026 330.5 INT-1048 (CIS)-3-(6- chloropyridin-3-yl)-8- (dimethylamino)-8-phenyl- 1,3-diazaspiro [4.5]decan-2-one

INT-989 385.2 INT-1049 (CIS)-3-(5- chloropyridin-2-yl)-8- (dimethylamino)- 8-phenyl-1,3- diazaspiro [4.5]decan-2-one

INT-989 385.2 INT-1061 TRANS-1- (cyclopropyl-methyl)-8- dimethylamino-8-phenyl- 1,3-diazaspiro [4.5]decan-2-one

INT-984 328.2 INT-1063 CIS-1- (cyclopropylmethyl)- 8-(dimethylamino)-8- (3-fluorophenyl)-1,3- diazaspiro[4.5] decan-2-one

INT-1031 346.2 INT-1066 TRANS-1- (cyclobutylmethyl)-8- (dimethylamino)-8-phenyl- 1,3-diazaspiro[4.5] decan-2-one

INT-987 342.3 INT-1070 CIS-8-(dimethylamino)- 8-phenyl-1-(3,3,3- trifluoropropyl)-1,3- diazaspiro[4.5]decan- 2-one

INT-1068 360.2 INT-1074 CIS-8-(dimethylamino)- 8-(3-fluorophenyl)-1-((1- hydroxycyclobutyl) methyl)-1,3- diazaspiro[4.5] decan-2-one

INT-1031 376.2 INT-1076 CIS-3-(2-chloro-4- methylpyrimidin-5-yl)-8- (dimethylamino)-8-(3- fluorophenyl)-1,3- diazaspiro[4.5] decan-2-one

INT-989 418.2 INT-1077 CIS-3-(4-chloro-2- (trifluoromethyl) pyrimidin-5- yl)-8-(dimethylamino)-8- (3-fluorophenyl)-1,3- diazaspiro[4.5] decan-2-one

INT-989 472.2 INT-1078 CIS-3-(4-chloro-2- cyclopropylpyrimidin- 5-yl)-8- (dimethylamino)-8- (3-fluorophenyl)-1,3- diazaspiro[4.5] decan-2-one

INT-989 444.2

Synthesis of Exemplary Compounds Synthesis of SC_3013: cis-5-[8-Dimethylamino-1-[(1-hydroxy-cyclobutyl)-methyl]-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-pyrimidine-2-carbonitrile

NaH (60% in mineral oil, 0.076 g, 3.19 mmol, 3 equiv.) was added to a solution of 5-(cis-8-(dimethylamino)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)pyrimidine-2-carbonitrile INT_600 (0.4 g, 1.06 mmol) in DMF (5 mL) at 0° C. The mixture was stirred for 30 min at RT and then cooled to 0° C. (1-(Tert-butyldimethylsilyloxy)cyclobutyl)methyl 4-methylbenzene-sulfonate (1.18 g, 3.19 mmol, 3 equiv.) was added dropwise over a period of 5 min and the reaction mixture was allowed to warm up to RT and further heated to 70° C. for 16 h. The reaction mixture was diluted with water (10 mL) and extracted with EtOAc (3×20 mL). The combined organic layers were dried over anhydrous Na₂SO₄ and the solvent was removed in vacuo. The residue was purified by silica gel flash chromatography to afford CIS-5-[8-dimethylamino-1-[(1-hydroxy-cyclobutyl)-methyl]-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-pyrimidine-2-carbonitrile (0.25 g).

Synthesis of SC_3014: cis-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-pyrimidine-5-carbonitrile

cis-1-(Cyclobutylmethyl)-8-(dimethylamino)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one INT-987 (500 mg, 1.464 mmol), 2-chloropyrimidine-5-carbonitrile (409 mg, 2.928 mmol) and Cs₂CO₃ (954 mg, 2.928 mmol) in 1,4-dioxane (6 ml) were stirred under an nitrogen atmosphere for 18 h at 105° C. The reaction mixture was cooled to RT, 2N aqueous NaOH solution (3 ml) was added and stirring was continued for 10 min. The mixture was extracted first with EtOAc and then with a blend of DCM (30 ml) and methanol (5 ml). The organic layers were combined and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel (elution with a DCM/EtOAc gradient) provided cis-2-[1-(cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-pyrimidine-5-carbonitrile SC_3014 (57 mg).

Synthesis of SC_3016: cis-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-pyrimidine-5-carboxylic Acid Amide

cis-2-[1-(Cyclobutylmethyl)-8-(dimethylamino)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]pyrimidine-5-carbonitrile SC_3014 (40 mg, 0.09 mmol) was dissolved in DMSO (1.2 mL) and K₂CO₃ (25 mg, 0.18 mmol) and hydrogen peroxide (30%, 0.13 mL 1.260 mmol) were added. The reaction mixture was stirred at RT for 20 h, then diluted with 2N NaOH (10 mL) and extracted with DCM (3×20 mL). The combined organic layers were dried over Na₂SO₄, concentrated in vacuo. The residue was purified by flash chromatography to yield cis-2-[1-(cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-pyrimidine-5-carboxylic acid amide SC_3016 (40 mg) as a white solid.

Synthesis of SC_3022: cis-1-(Cyclobutylmethyl)-8-(dimethylamino)-8-phenyl-3-[2-(trifluoromethyl)pyrimidin-5-yl]-1, 3-diazaspiro[4.5]decan-2-one

cis-1-(Cyclobutylmethyl)-8-(dimethylamino)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one INT-987 (240 mg, 0.7 mmol), Pd-XPhos Generation 2 (138 mg, 0.17 mmol), Cs₂CO₃ (457 mg, 1.4 mmol) and 5-bromo-2-(trifluoromethyl)pyrimidine (319 mg, 1.4 mmol) were suspended in anhydrous 1,4-dioxane (3 mL) under nitrogen atmosphere and the resulting mixture was stirred at 100° C. overnight. The reaction mixture was cooled to RT and water (3 mL) was added. The aqueous layer was extracted with DCM (3×10 mL), the combined organic layers were dried over Na₂SO₄ and concentrated in vacuo. The residue was purified by flash chromatography on silica gel to yield the title compound. Final purification using a strong cation exchange resin gave cis-1-(cyclobutylmethyl)-8-(dimethylamino)-8-phenyl-3-[2-(trifluoromethyl)pyrimidin-5-yl]-1,3-diazaspiro[4.5]decan-2-one SC_3022 (145 mg) as a white solid.

Synthesis of SC_3028: cis-4-[1-(cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N,N-dimethyl-benzamide

Step 1: Lithium 4-(cis-1-(cyclobutylmethyl)-8-(dimethylamino)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)benzoate

Methyl 4-(cis-1-(cyclobutylmethyl)-8-(dimethylamino)-2-oxo-8-phenyl-1,3-diazaspiro [4.5]decan-3-yl)benzoate SC_3081 (400 mg) was dissolved in methanol (5 mL) and DCM (5 mL). Lithium hydroxide solution (2 M in water, 1 mL) was added and the resulting mixture was stirred overnight at RT. All volatiles were removed in vacuo to yield lithium 4-(cis-1-(cyclobutylmethyl)-8-(dimethylamino)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)benzoate (403 mg).

Step 2 cis-4-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro [4.5]decan-3-yl]-N,N-dimethyl-benzamide (SC_3028)

Lithium 4-(cis-1-(cyclobutylmethyl)-8-(dimethylamino)-2-oxo-8-phenyl-1,3-diazaspiro [4.5]decan-3-yl)benzoate (80 mg, 0.17 mmol) was suspended in DCM (1 mL) and triethylamine (0.23 mL, 1.7 mmol) and dimethylamine (2M solution in THF, 0.17 mL) and T3P (0.20 mL, 0.34 mmol) were sequentially added. The resulting mixture was stirred for 18 h at RT. Water (10 mL) was added and the mixture was extracted with DCM (3×20 mL). The combined organic layers were dried over Na₂SO₄, concentrated in vacuo and the residue was purified by flash chromatography to yield cis-4-[1-(cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N,N-dimethyl-benzamide SC_3028 (28 mg) as white solid.

Synthesis of SC_3045: cis-4-Methoxy-5-[1-(3-methoxypropyl)-8-(methylamino)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]pyrimidine-2-carbonitrile

N-iodosuccinimide (150 mg, 0.67 mmol) was added to a suspension of cis-5-[8-(dimethylamino)-1-(3-methoxypropyl)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-4-methoxy-pyrimidine-2-carbonitrile SC_3040 (214 mg, 0.44 mmol) in acetonitrile/THF (2/1 v/v, 10 mL) at RT and the resulting mixture was stirred for 16 h at RT. The reaction mixture was basified with 2N NaOH solution to pH10 and the organic product was extracted with DCM (10 mL×3). The combined organic extracts were dried over anhydrous Na₂SO₄, the solvent was removed in vacuo and the residue was purified by preparative flash chromatography to give cis-4-methoxy-5-[1-(3-methoxypropyl)-8-(methylamino)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]pyrimidine-2-carbonitrile SC_3045 (81 mg) as a solid.

Synthesis of SC_3064: cis-2-[3-(2-cyano-pyrimidin-5-yl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-1-yl]-N-propyl-acetamide

Sodium hydroxide (51 mg, 1.3 mmol) was added to anhydrous DMSO (4.5 mL) and stirred for 10 minutes at room temperature. cis-5-[8-(Dimethylamino)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]pyrimidine-2-carbonitrile INT_600 (80 mg, 0.21 mmol) was added and the resulting mixture was stirred at room temperature for 5 min and then heated to 50° C. 2-Bromo-N-propyl-acetamide (153 mg, 0.85 mmol) was added and stirring was continued at 50° C. for one hour. The reaction mixture was quenched with water (25 mL) and extracted with ethyl acetate (2×10 mL). The combined organic layers were washed with water (5 mL) and brine (5 mL), dried over Na₂SO₄ and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel to yield cis-2-[3-(2-cyano-pyrimidin-5-yl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-1-yl]-N-propyl-acetamide SC_3064 (22 mg) as a solid.

Synthesis of SC_3065: 5-(cis-1-(Cyclobutylmethyl)-8-(ethyl(methyl)amino)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)-4-methoxypyrimidine-2-carbonitrile

Cs₂CO₃ (274 mg, 0.84 mmol) was added to the solution of cis-1-(cyclobutylmethyl)-8-(ethyl(methyl)amino)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one INT_986 (150 mg, 0.42 mmol), Xanthphos (36 mg, 0.063 mmol), Pd₂(dba)₃ (19 mg, 0.0211 mmol) and 5-bromo-4-methoxypyrimidine-2-carbonitrile (135 mg, 0.633 mmol) in 1,4-dioxane (10 mL) under argon atmosphere. The mixture was flushed again with argon for 5 min and the reaction mixture was stirred at 90° C. for 5h. The reaction mixture was cooled to room temperature. The residue was diluted with water (20 mL) and the organic product was extracted with ethyl acetate (3×10 mL). The combined organic extracts were dried over anhydrous Na₂SO₄ and the solvent was concentrated under reduced pressure. The residue was purified by preparative TLC (EtOAc/petroleum ether 1/9) to afford a white solid (0.15 g), which was further washed with n-pentane to give 0.1 g of 5-(cis-1-(cyclobutylmethyl)-8-(ethyl(methyl)amino)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)-4-methoxypyrimidine-2-carbonitrile SC_3065.

Synthesis of SC_3008: cis-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-5-methylsulfonyl-benzonitrile

cis-2-[1-(Cyclobutylmethyl)-8-(dimethylamino)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-5-methylsulfanyl-benzonitrile (320 mg, 0.66 mmol, prepared from 2-iodo-5-(methylthio)benzonitrile and INT-987 analogously to SC_3022) was dissolved in a mixture of methanol (9 mL) and water (8 mL). Oxone® (807 mg, 1.3 mmol) was added at RT and the resulting mixture was stirred at RT for 18 h. Water (10 mL) was added and the mixture was extracted with DCM (3×20 mL). The combined organic layers were dried over Na₂SO₄, concentrated in vacuo. The residue was purified by flash chromatography on silica gel to yield cis-2-[1-(cyclobutylmethyl)-8-(dimethylamino)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-5-methylsulfonyl-benzonitrile SC_3008 (66 mg) as a white solid.

Synthesis of SC_3023: cis-8-Dimethylamino-1-[(1-hydroxy-cyclobutyl)-methyl]-3-(2-hydroxy-pyrimidin-5-yl)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one

Boron tribromide (1M in DCM, 0.38 mL, 0.387 mmol) was added to the solution of cis-8-dimethylamino-1-[(1-hydroxy-cyclobutyl)-methyl]-3-(2-methoxy-pyrimidin-5-yl)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one SC_3015 (180 mg, 0.387 mmol) in DCM (2 mL) at 0° C. The reaction mixture was stirred for 30 min at 0° C. and then for 16 h at room temperature, quenched with methanol (2 mL), the solvents were removed under reduced pressure and the residue was purified by normal phase preparative HPLC to yield cis-8-dimethylamino-1-[(1-hydroxy-cyclobutyl)-methyl]-3-(2-hydroxy-pyrimidin-5-yl)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one SC_3023 (60 mg, 34%) as a white solid. ¹H NMR (400 MHz, DMSO-d₆, δ in ppm): 6 8.43 (s, 2H), 7.35-7.25 (m, 5H), 5.50 (s, 1H), 3.67 (s, 2H), 3.19 (s, 2H), 2.69-2.65 (m, 2H), 2.19-2.10 (m, 4H), 1.98-1.85 (m, 8H), 1.68-1.61 (m, 1H), 1.51-1.39 (m, 5H).

Synthesis of SC_3025: cis-5-[8-Dimethylamino-1-(2-hydroxy-ethyl)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-pyrimidine-2-carbonitrile

Step 1: 5-(cis-1-(2-(tert-Butyldimethylsilyloxy)ethyl)-8-(dimethylamino)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)pyrimidine-2-carbonitrile

NaH (60% in mineral oil, 63.8 mg, 1.59 mmol) was added at 0° C. to the solution of 5-(cis-8-(dimethylamino)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)pyrimidine-2-carbonitrile INT-600 (0.2 g, 0.53 mmol) in DMF (8 mL) for 10 min at 0° C. The reaction mixture was stirred at RT for 30 min, (3-bromopropoxy)(tert-butyl)dimethylsilane (252 mg, 1.06 mmol) was added dropwise over 5 min at 0° C. and the mixture was stirred for further 16 h at RT. The reaction mixture was diluted with water (15 mL) and extracted with diethyl ether (3×25 mL). The combined organic extracts were dried over anhydrous Na₂SO₄, the solvents were removed under reduced pressure and the residue was purified by flash chromatography on silica gel to afford 5-(cis-1-(2-(tert-butyldimethylsilyloxy)ethyl)-8-(dimethylamino)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)pyrimidine-2-carbonitrile (100 mg, 34%) as a white solid.

Step 2: cis-5-[8-Dimethylamino-1-(2-hydroxy-ethyl)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-pyrimidine-2-carbonitrile (SC_3025)

1M TBAF solution in THF (0.36 mL, 0.36 mmol) was added to 5-(cis-1-(2-(tert-butyldimethylsilyloxy)ethyl)-8-(dimethylamino)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)pyrimidine-2-carbonitrile (0.1 g, 0.18 mmol) in THF (5 mL) at 0° C. The reaction mixture was stirred at RT for 30 min, diluted with water (10 mL) and extracted with diethyl ether (3×25 mL). The combined organic extracts were washed with sat. aq. NaHCO₃, water and brine and dried over anhydrous Na₂SO₄. The solvents were evaporated under reduced pressure and the residue was purified by preparative TLC (ethyl acetate/n-hexane=45:55) and then washed with n-pentane (5 mL) to give of cis-5-[8-dimethylamino-1-(2-hydroxy-ethyl)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-pyrimidine-2-carbonitrile (70 mg, 80%) as a white solid. ¹H NMR (400 MHz, DMSO-d₆, δ in ppm): δ 9.18 (s, 2H), 7.38-7.26 (m, 5H), 4.84 (t, 1H), 3.82 (s, 2H), 3.55-3.51 (m, 2H), 3.26-3.20 (m, 2H), 2.73-2.70 (m, 2H), 2.17-2.11 (m, 2H), 2.00 (s, 6H), 1.57-1.43 (m, 4H).

Synthesis of SC_3097: CIS-8-dimethylamino-1-[(1-hydroxy-cyclobutyl)-methyl]-3-(2-morpholin-4-yl-pyrimidin-5-yl)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one

starting from here until the end of the section all procedures were added

Step 1: 4-(5-bromopyrimidin-2-yl)morpholine

K₂CO₃ (14.2 g, 103 mmol) was added to the solution of morpholine (9.0 g, 103 mmol) in acetonitrile (900 mL) and the resulting suspension was stirred at RT for 1 h. 5—Bromo-2-chloropyrimidine (20 g, 103 mmol) was added portionwise. The reaction mixture was stirred for 16h at 80° C., then cooled down to RT and diluted with EtOAc (100 mL) and water (50 mL). The organic product was extracted with EtOAc (2×100 mL). The combined organic layer was washed with brine (100 mL), dried over anhydrous Na₂SO₄ and concentrated under reduced pressure. The resulting residue was purified by column chromatography on silica gel (100-200 mesh) (20% EtOAc in petroleum ether) to afford 18.0 g (71%) of 4-(5-bromopyrimidin-2-yl)morpholine as an off white solid (TLC system: 30% EtOAc in pet ether, R_(f): 0.6).

Step 2: CIS-8-dimethylamino-1-[(1-hydroxy-cyclobutyl)-methyl]-3-(2-morpholin-4-yl-pyrimidin-5-yl)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one (SC_3097)

K₂CO₃ (0.53 g, 3.85 mmol, 2.5 equiv.) was added to the suspension of CIS-8-(dimethylamino)-1-((1-hydroxycyclobutyl)methyl)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one (INT-799) (0.55 g, 1.54 mmol, 1 equiv.) and 4-(5-bromopyrimidin-2-yl)morpholine (0.37 g, 1.54 mmol, 1 equiv.) in dioxane (20 mL) and the resulting suspension was purged with nitrogen for 5 min. Copper(I) iodide (0.29 g, 1.54 mmol, 1 equiv.) and trans-1,2-diaminocyclohexane (0.35 g, 3.085 mmol, 2 equiv.) were sequentially added, the reaction vessel was sealed and the reaction mixture was stirred at 130° C. for 4 h. The reaction mixture was cooled down to RT and diluted with EtOAc (20 mL) and aq. ammonia (10 mL). The organic product was extracted with EtOAc (2×50 mL). The combined organic layer was washed with brine (50 mL), dried over anhydrous Na₂SO₄ and concentrated under reduced pressure. Purification of the resulting residue by column chromatography on silica gel (100-200 mesh) (60-70% EtOAc in petroleum ether) afforded 0.35 g (48%) of CIS-8-(dimethylamino)-1-((1-hydroxycyclobutyl)methyl)-3-(2-morpholin-4-yl-pyrimidin-5-yl)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one (SC_3097) as an off white solid (TLC system: EtOAc, R_(f): 0.7). ¹H NMR (DMSO-d₆): δ 8.60 (s, 2H), 7.36-7.35 (m, 4H), 7.27-7.24 (m, 1H), 5.50 (s, 1H), 3.72 (s, 2H), 3.62-3.61 (m, 8H), 3.21 (s, 2H), 2.70-2.66 (m, 2H), 2.19-2.11 (m, 4H), 1.98 (s, 6H), 1.93-1.85 (m, 2H), 1.66-1.64 (m, 1H), 1.53-1.42 (m, 5H). Mass: m/z 521.3 (M+H)⁺.

Synthesis of SC_3099: CIS-1-[(1-hydroxy-cyclobutyl)-methyl]-8-methylamino-3-(2-morpholin-4-yl-pyrimidin-5-yl)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one

N-Iodosuccinimide (162 mg, 0.72 mmol) was added to the solution CIS-8-(dimethylamino)-1-((1-hydroxycyclobutyl)methyl)-3-(2-morpholinopyrimidin-5-yl)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one (SC-3097) (250 mg, 0.48 mmol) in acetonitrile (8.0 mL) and THF (8.0 mL) at 0° C. and the resulting mixture was stirred for 16 h at RT. The reaction mixture was concentrated under reduced pressure. The residue was dissolved in EtOAc (2×30 mL), the organic layer was washed with 2N aq. NaOH solution, dried over anhydrous Na₂SO₄ and concentrated under reduced pressure. The residue was purified by reverse phase prep. HPLC to yield 0.12 g (49%) of CIS-1-((1-hydroxycyclobutyl)methyl)-8-(methylamino)-3-(2-morpholinopyrimidin-5-yl)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one (SC_3099) as an off white solid (TLC system 5% MeOH in DCM R_(f): 0.5.). Preparative reverse phase HPLC conditions: column: Luna-Phenyl-Hexyl-C18 (150*19 mm) 5 μm; mobile phase: 10 mM ammonium bicarbonate/acetonitrile, gradient (T/% B): 0/50, 7/85, 7.1/98, 9/98, 9.1/50, 12/50; flow Rate: 25 ml/min; diluent: mobile phase+THF. ¹H NMR (DMSO-d6): δ 8.63 (s, 2H), 7.49-7.47 (m, 2H), 7.34-7.30 (t, 2H), 7.21-7.17 (m, 1H), 5.60 (s, 1H), 3.76 (s, 2H), 3.64-3.62 (m, 8H), 3.35 (m, 2H), 2.26-2.20 (m, 3H), 2.12-2.08 (m, 2H), 1.90-1.88 (m, 7H), 1.79-1.73 (m, 2H), 1.65-1.63 (m, 1H), 1.52-1.44 (m, 3H). Mass: m/z 507.3 (M+H)⁺.

Synthesis of SC_3100: CIS-8-dimethylamino-1-[(1-hydroxy-cyclobutyl)-methyl]-8-phenyl-3-(2-piperazin-1-yl-pyrimidin-5-yl)-1,3-diazaspiro[4.5]decan-2-one Hydrochloride

Step 1: tert-butyl 4-(5-bromopyrimidin-2-yl)piperazine-1-carboxylate

In analogy to the method described for SC_3097 step 1 tert-butyl piperazine-1-carboxylate was reacted with 5-bromo-2-chloropyrimidine to be converted into tert-butyl 4-(5-bromopyrimidin-2-yl)piperazine-1-carboxylate.

Step 2: tert-butyl 4-(5-((cis)-8-(dimethylamino)-1-((1-hydroxycyclobutyl)methyl)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)pyrimidin-2-yl)piperazine-1-carboxylate

K₂CO₃ (0.38 g, 2.8 mmol, 2.5 equiv.) was added to the suspension of CIS-8-(dimethylamino)-1-((1-hydroxycyclobutyl)methyl)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one (0.4 g, 1.12 mmol, 1 equiv.) (INT-799) and tert-butyl 4-(5-bromopyrimidin-2-yl)piperazine-1-carboxylate (0.38 g, 1.12 mmol, 1 equiv.) in dioxane (25 mL) and the resulting mixture was purged with nitrogen for 5 min. Copper(I) iodide (0.21 g, 1.12 mmol, 1 equiv.) and trans-1,2-diaminocyclohexane (0.25 g, 2.24 mmol, 2 equiv.) were sequentially added, the reaction vessel was sealed and the reaction mixture was stirred for 10h at 130° C. The reaction mixture was cooled down to RT and diluted with EtOAc (20 mL) and aq. ammonia (10 mL). The organic product was extracted with e EtOAc (2×50 mL). The combined organic layer was washed with brine (50 mL), dried over anhydrous Na₂SO₄ and concentrated under reduced pressure. Purification of the residue by column chromatography on silica gel (100-200 mesh) (60-70% EtOAc in petroleum ether) afforded 0.5 g (72%) of tert-butyl 4-(5-((cis)-8-(dimethylamino)-1-((1-hydroxycyclobutyl)methyl)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)pyrimidin-2-yl)piperazine-1-carboxylate as an off white solid (TLC system: 1:1 EtOAc/pet ether, R_(f): 0.3).

Step 3: CIS-8-(dimethylamino)-1-((1-hydroxycyclobutyl)methyl)-8-phenyl-3-(2-(piperazin-1-yl)pyrimidin-5-yl)-1,3-diazaspiro[4.5]decan-2-one hydrochloride (SC_3100)

4N HCl in dioxane (2 mL) was added to tert-butyl 4-(5-(cis-8-(dimethylamino)-1-((1-hydroxycyclobutyl)methyl)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)pyrimidin-2-yl)piperazine-1-carboxylate (0.15 g, 0.24 mmol). The resulting mixture was stirred at 0° C. for 6 h and then concentrated under reduced pressure to give a pale yellow solid which was triturated with n-pentane and lyophilized with water for 16 h to yield 0.14 g of CIS-8-(dimethylamino)-1-((1-hydroxycyclobutyl)methyl)-8-phenyl-3-(2-(piperazin-1-yl)pyrimidin-5-yl)-1,3-diazaspiro[4.5]decan-2-one hydrochloride (SC_3100) as a pale yellow solid. ¹H NMR (DMSO-d6): δ 10.42 (br s, 1H), 9.34 (br s, 2H), 8.63 (s, 2H), 7.70-7.68 (m, 2H), 7.54-7.50 (m, 3H), 3.88-3.86 (m, 4H), 3.77 (m, 4H), 3.16-3.11 (m, 6H), 2.52-2.49 (m, 6H), 2.47 (m, 2H), 2.10-2.07 (m, 2H), 2.00-1.95 (t, 2H), 1.87-1.81 (m, 3H), 1.70-1.68 (m, 2H), 1.58 (m, 1H). Mass: m/z 520.3 (M+H)⁺.

Synthesis of SC_3103: CIS-1-(cyclobutyl-methyl)-8-dimethylamino-3-[4-methyl-6-(trifluoromethyl)-pyridin-3-yl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one

Cs₂CO₃ (2 g, 6.451 mmol) was added to an argon purged solution of CIS-1-(cyclobutylmethyl)-8-(dimethylamino)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one (INT-987) (1.1 g, 3.225 mmol, 1 equiv.), Xantphos (279 mg, 0.483 mmol, 0.15 equiv.), Pd₂(dba)₃ (295 mg, 0.322 mmol, 0.1 equiv.) and 5-bromo-4-methyl-2-(trifluoromethyl)pyridine (774 mg, 3.225 mmol, 1 equiv.) in 1,4-dioxane (55 mL). The mixture was purged again with argon for 15 min. The reaction mixture was stirred at 90° C. for 18 h, then cooled down to RT, filtered through Celite and washed with EtOAc (80 mL). The filtrate was concentrated under reduced pressure. The resulting residue was purified by flash chromatography (neutral alumina, 0-3% methanol in DCM) to afford 0.6 g (37%) of CIS-1-(cyclobutylmethyl)-8-(dimethylamino)-3-(4-methyl-6-(trifluoromethyl)pyridin-3-yl)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one (SC_3103) as an off white solid. (TLC system: 5% MeOH in DCM; Rf: 0.5). ¹H NMR (DMSO-d6): δ 8.56 (s, 1H), 7.80 (s, 1H), 7.34-7.24 (m, 5H), 3.71 (s, 2H), 3.17 (d, 2H), 2.70-2.56 (m, 3H), 2.31 (s, 3H), 2.17-2.11 (m, 2H), 2.03-2.00 (m, 8H), 1.82-1.73 (m, 4H), 1.54-1.41 (m, 4H). Mass: m/z 501.3 (M+H)⁺.

Synthesis of SC_3105: CIS-1-(cyclopropyl-methyl)-8-dimethylamino-3-(4-methylsulfonyl-phenyl)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one

NaH (60% in mineral oil) (36.80 mg, 0.92 mmol) was added portionwise to the solution of CIS-8-(dimethylamino)-3-(4-(methylsulfonyl)phenyl)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one (200 mg, 0.46 mmol, prepared from INT-976 and 1-bromo-4-(methylsulfonyl)benzene by analogy with SC_3103) in DMF (30 mL) at 0° C. under argon atmosphere and the resulting mixture was stirred for 10 min. (Bromomethyl)cyclopropane (122 mg, 0.92 mmol) was added dropwise at 0° C., ice bath was removed and the reaction mixture was further stirred for 4h at room temperature. The reaction progress was monitored by TLC. The reaction mixture was diluted with water (30 mL) and the precipitated solid was filtered. Purification by column chromatography (silica gel 100-200mesh, 50-60% ethyl acetate in hexane as eluent) to get 80 mg (35%) of CIS-1-(cyclopropylmethyl)-8-(dimethylamino)-3-(4-(methylsulfonyl)phenyl)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one (SC_3105) as off white solid (TLC system: 10% MeOH in DCM; R_(f): 0.70). 1H NMR (CDCl3): δ 7.85-7.83 (d, 2H), 7.73-7.71 (d, 2H), 7.39-7.36 (m, 2H), 7.32-7.27 (m, 3H), 3.64 (s, 2H), 3.20 (d, 2H), 3.00 (s, 3H), 2.75-2.71 (m, 2H), 2.43-2.36 (m, 2H), 2.07 (s, 6H), 1.57 (m, 2H), 1.50 (m, 2H), 1.11-1.06 (m, 1H), 0.59-0.54 (m, 2H), 0.41-0.37 (m, 2H). Mass: m/z 482.2 (M+H)⁺.

Synthesis of SC_3109: CIS-2-[8-Dimethylamino-1-[2-(1-methoxy-cyclobutyl)-ethyl]-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-benzamide

Step 1: CIS-2-(8-(dimethylamino)-1-(2-(1-methoxycyclobutyl)ethyl)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)benzonitrile

In analogy to the method described for SC_3103 CIS-8-(dimethylamino)-1-(2-(1-methoxycyclobutyl)ethyl)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one was reacted with 2-bromobenzonitrile to be converted into CIS-2-(8-(dimethylamino)-1-(2-(1-methoxycyclobutyl)ethyl)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)benzonitrile.

Step 2: CIS-2-[8-Dimethylamino-1-[2-(1-methoxy-cyclobutyl)-ethyl]-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-benzamide SC_3109

CIS-2-[8-(dimethylamino)-1-[2-(1-methoxycyclobutyl)ethyl]-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]benzonitrile (57.0 mg, 1.0 equiv.) was dissolved in DMSO (1.6 mL), hydrogen peroxide (0.167 mL, 14.0 equiv., 30 mass % in water solution) and K₂CO₃ (32.4 mg, 2.0 equiv.) were added and the reaction mixture was stirred at RT for 18 h. The reaction mixture was then quenched with 10 mL water, extracted with DCM (3×10 mL), the combined organic extracts were dried over Na₂SO₄ and concentrated under reduced pressure (24 mg crude product). The aqueous phase was concentrated to dryness (91 mg), suspended in DCM, the precipitate was filtered off and the organic solution was concentrated under reduced pressure to give additional 56 mg of the crude product. The combined crude product was purified by column chromatography on silica gel (DCM/EtOH 95/5) to give 37 mg (62%) of CIS-2-[8-dimethylamino-1-[2-(1-methoxy-cyclobutyl)-ethyl]-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-benzamide (SC_3109) as a white solid. ¹H NMR (600 MHz, DMSO) δ 7.52-7.48 (s, 1H), 7.47-7.31 (m, 7H), 7.29-7.23 (m, 1H), 7.25-7.22 (s, 1H), 7.24-7.18 (m, 1H), 3.68-3.65 (s, 3H), 3.13-3.10 (s, 2H), 3.09-3.02 (m, 2H), 2.71-2.65 (m, 2H), 2.21-2.12 (m, 2H), 2.09-1.99 (m, 2H), 2.02-1.98 (s, 6H), 1.97-1.86 (m, 4H), 1.77-1.67 (m, 1H), 1.64-1.52 (m, 3H), 1.44-1.36 (td, 2H). Mass: m/z 505.32 (M+H)*.

Synthesis of SC_3112: CIS-2-(1-((1-hydroxycyclobutyl)methyl)-8-(methylamino)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)benzonitrile

Step 1: CIS-2-(8-(dimethylamino)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)benzonitrile

In analogy to the method described for SC_3103 1-bromo-2-cyanobenzene was reacted with CIS-8-(dimethylamino)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one (INT-976) to be converted into CIS-2-(8-(dimethylamino)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)benzonitrile.

Step 2: CIS-2-(8-(dimethylamino)-1-((1-hydroxycyclobutyl)methyl)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)benzonitrile

To a solution of CIS-2-(8-(dimethylamino)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)benzonitrile (500 mg, 1.336 mmol, 1.0 equiv.) in DMSO (16 ml) was added sodium hydroxide (213 mg, 5.334 mmol, 4.0 equiv.) and the mixture was stirred at 60° C. for 30 min. A solution of 1-oxa-spiro[2.3]hexane (237 mg, 6.68 mmol, 5.0 equiv.) in DMSO (4 ml) was added at RT and the reaction mixture was stirred at 55° C. for 16h. The reaction mixture was diluted with water (100 ml) and extracted with EtOAc (100 ml). The organic layer was washed with water (50 ml) and brine (50 ml), dried over anhydrous Na₂SO₄ and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (EtOAc/Hexane, 7/3) to yield CIS-2-(8-(dimethylamino)-1-((1-hydroxycyclobutyl)methyl)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)benzonitrile (200 mg, 0.436 mmol, 32%) as an off white solid. Mass: m/z 459.4 (M+H)+

Step 3: CIS-2-(1-((1-hydroxycyclobutyl)methyl)-8-(methylamino)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)benzonitrile (SC_3112)

In analogy to the method described for SC_3099 CIS-2-(8-(dimethylamino)-1-((1-hydroxycyclobutyl)methyl)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)benzonitrile was reacted with N-iodosuccinimide to be converted into CIS-2-(1-((1-hydroxycyclobutyl)methyl)-8-(methylamino)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)benzonitrile (SC_3112). Yield: 29%. ¹H NMR (DMSO-d6, 400 MHz), δ (ppm)=7.75 (dd, 1H, J=7.76 Hz, 1.16 Hz), 7.70-7.65 (m, 1H), 7.50 (d, 1H, J=8.16 Hz), 7.44-7.42 (m, 2H), 7.35-7.25 (m, 3H), 7.17-7.15 (m, 1H), 5.49 (s, 1H), 3.85 (s, 2H), 3.32 (s, 2H), 2.29-2.23 (m, 2H), 2.12-2.23 (m, 2H), 1.87 (bs, 6H), 1.73-1.46 (m, 6H). Mass: m/z 445.26 (M+H)⁺.

Synthesis of SC_3120: CIS-8-(dimethylamino)-3-(2-(3-oxopiperazin-1-yl)pyrimidin-5-yl)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one

CIS-3-(2-chloropyrimidin-5-yl)-8-(dimethylamino)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one (INT-989) (100 mg, 0.259 mmol) was placed into a reaction vial for microwave reactor (5 mL), the vial was flushed with nitrogen, anhydrous n-butanol (50 equiv., 13.0 mmol, 1.2 mL), diisopropylethylamine (5 equiv., 1.30 mmol, 0.224 mL) and piperazine-2-one (1.2 equiv., 0.311 mmol, 31 mg) were added, the vial was sealed and the reaction mixture was stirred for 2.5 h at 140° C. (conventional heating). The reaction mixture was cooled down, transferred into a 1-neck flask and concentrated under reduced pressure. The resulting residue (128 mg) was purified by flash chromatography on aluminium oxide (neutral) (DCM/MeOH gradient 100/0 to 97/3) to yield 65 mg (56%) CIS-8-(dimethylamino)-3-(2-(3-oxopiperazin-1-yl)pyrimidin-5-yl)-8-phenyl-1,3-diazaspiro-[4.5]decan-2-one (SC_3120). ¹H NMR (600 MHz, DMSO) δ 8.60 (s, 2H), 8.01 (s, 1H), 7.46 (s, 1H), 7.43-7.30 (m, 4H), 7.27 (td, 1H), 4.09 (s, 2H), 3.91-3.75 (m, 2H), 3.62-3.40 (m, 2H), 3.30-3.09 (m, 2H), 2.61-2.51 (m, 2H), 2.44-2.25 (m, 2H), 1.97 (s, 6H), 1.93-1.80 (m, 2H), 1.55-1.41 (m, 2H). Mass: m/z 437.27 (M+H)⁺.

Synthesis of SC_3129: CIS-3-(5-(8-(dimethylamino)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)pyrimidin-2-yl)benzonitrile

CIS-3-(2-chloropyrimidin-5-yl)-8-(dimethylamino)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one (INT-989) (1 equiv., 0.47 mmol, 180 mg), Pd(PPh₃)₄ (0.1 equiv., 0,047 mmol, 54 mg) and (3-cyanophenyl)boronic acid (1.5 equiv., 0.70 mmol, 103 mg) were dissolved in degassed dry tetrahydrofurane (9.5 mL) and sodium carbonate 1M aq. sol. (1.9 equiv., 0.89 mmol, 0.89 mL) was added. The resulting clear reaction mixture was stirred overnight at 70° C. Additional portion of Pd(PPh₃)₄ (0.1 equiv., 0,047 mmol, 54 mg) was added and the reaction was stirred further 12 h at 70° C. The reaction mixture was diluted with EtOAc (50 mL), stirred for 10 min, the precipitate was filtered off and the filtrate was concentrated under reduced pressure. The resulting residue (285 mg) was purified by flash chromatography on silica gel (gradient DCM/MeOH, 100/0 to 80/20) to yield 130 mg (62%) of CIS-3-(5-8-(dimethylamino)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)pyrimidin-2-yl)benzonitrile (SC_3129). ¹H NMR (600 MHz, DMSO) δ 9.13 (s, 2H), 8.60 (dp, 2H), 7.93 (dt, 1H), 7.88 (s, 1H), 7.72 (dd, 1H), 7.42-7.35 (m, 5H), 7.28 (d, 1H), 3.73 (s, 2H), 2.01-1.91 (m, 2H), 1.98 (s, 10H), 1.57-1.48 (m, 2H). Mass: m/z 453.24 (M+H)⁺.

Synthesis of SC_3130: CIS-8-(dimethylamino)-3-(2-(4-(methylsulfonyl)piperazin-1-yl)pyrimidin-5-yl)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one

CIS-8-(dimethylamino)-8-phenyl-3-(2-(piperazin-1-yl)pyrimidin-5-yl)-1,3-diazaspiro[4.5]decan-2-one (SC_3124) (100 mg, 0.23 mmol) was dissolved in DCM (150 equiv., 34 mmol, 2.2 mL) under nitrogen atmosphere. To the resulting solution 4-dimethylaminopyridine (0.05 equiv., 0.012 mmol, 1.4 mg) and diisopropylethylamine (3 equiv., 0.67 mmol, 0.119 mL) were added and the mixture was cooled to 0° C. Methansulfonylchloride (2 equiv., 0.46 mmol, 0.036 mL) was added, ice bath was removed and the reaction mixture was stirred for 2 h at RT. The reaction mixture was quenched with water (5 mL), diluted with DCM (10 mL), the resulting brown suspension was filtered through a glass filter, the filtrate transferred to a separating funnel, the organic phase separated and the aqueous phase extracted with DCM (2×10 mL). The combined organic phases were dried over MgSO₄ and concentrated under reduced pressure. The resulting residue (81 mg) was purified by flash chromatography on aluminium oxide (gradient DCM/EtOH 97/3 to 96/4) to yield 51 mg (43%) of CIS-8-(dimethylamino)-3-(2-(4-(methylsulfonyl)piperazin-1-yl)pyrimidin-5-yl)-8-phenyl-1,3-diazaspiro-[4.5]decan-2-one (SC_3130). ¹H NMR (600 MHz, DMSO) δ 8.59 (s, 2H), 7.46 (s, 1H), 7.39 (d, 1H), 7.37 (s, 3H), 7.28 (d, 1H), 3.79-3.74 (m, 4H), 3.54 (s, 2H), 3.18-3.13 (m, 4H), 2.87 (s, 3H), 2.43-2.32 (m, 2H), 1.97 (s, 6H), 1.92-1.87 (m, 2H), 1.51-1.41 (m, 2H). Mass: m/z 514.26 (M+H)⁺.

Synthesis of SC_3132: CIS-8-((cyclopropylmethyl)(methyl)amino)-8-phenyl-3-(2-(trifluoromethyl)pyrimidin-5-yl)-1,3-diazaspiro[4.5]decan-2-one

Step 1: CIS-8-(methylamino)-8-phenyl-3-(2-(trifluoromethyl)pyrimidin-5-yl)-1,3-diazaspiro[4.5]decan-2-one

In analogy to the method described for SC_3099 CIS-8-(dimethylamino)-8-phenyl-3-(2-(trifluoromethyl)pyrimidin-5-yl)-1,3-diazaspiro[4.5]decan-2-one (SC_3245) was reacted with N-iodosuccinimide to be converted into CIS-8-(methylamino)-8-phenyl-3-(2-(trifluoromethyl)pyrimidin-5-yl)-1,3-diazaspiro[4.5]decan-2-one.

Step 2: CIS-1-(4-methoxybenzyl)-8-(methylamino)-8-phenyl-3-(2-(trifluoromethyl)pyrimidin-5-yl)-1,3-diazaspiro[4.5]decan-2-one

NaH (60% in mineral oil) (296.3 mg, 7.407 mmol, 1.5 equiv.) was added portionwise to the solution CIS-8-(methylamino)-8-phenyl-3-(2-(trifluoromethyl)pyrimidin-5-yl)-1,3-diazaspiro[4.5]decan-2-one (2 g, 4.938 mmol, 1 equiv.) in DMF (20 mL) at 0° C. under argon atmosphere and the resulting mixture was stirred for 10 min. 1-(Bromomethyl)-4-methoxybenzene (1.092 g, 5.432 mmol, 1.1 equiv.) was added dropwise. The reaction mixture was allowed to warm up to RT and stirred for 16h. The reaction progress was monitored by LCMS. The reaction mixture was diluted with water (150 mL) and the organic product was extracted with EtOAc (3×60 mL). The combined organic extracts were dried over anhydrous Na₂SO₄ and concentrated under reduced pressure. The resulting residue was purified by flash chromatography (silica gel 230-400 mesh; 04% MeOH/DCM) to afford 2 g (77%) of CIS-1-(4-methoxybenzyl)-8-(methylamino)-8-phenyl-3-(2-(trifluoromethyl)pyrimidin-5-yl)-1,3-diazaspiro[4.5]decan-2-one as an off white solid (TLC system 5% MeOH in DCM R_(f): 0.55).

Step 3: CIS-8-((cyclopropylmethyl)(methyl)amino)-1-(4-methoxybenzyl)-8-phenyl-3-(2-(trifluoromethyl)pyrimidin-5-yl)-1,3-diazaspiro[4.5]decan-2-one

(Bromomethyl)cyclopropane (0.461 mL, 4.762 mmol, 5 equiv.) was added dropwise to a mixture of CIS-1-(4-methoxybenzyl)-8-(methylamino)-8-phenyl-3-(2-(trifluoromethyl)pyrimidin-5-yl)-1,3-diazaspiro-[4.5]decan-2-one (500 mg, 0.952 mmol, 1 equiv.) and K₂CO₃ (657 mg, 4.762 mmol, 5 equiv.) in acetonitrile (20 mL) at RT under argon atmosphere. The reaction vessel was sealed and the mixture was stirred at 95° C. for 24h. Reaction progress was monitored by LCMS. The reaction mixture was diluted with water (50 mL) and the organic product was extracted with EtOAc (2×50 mL). The combined organic extracts were dried over anhydrous Na₂SO₄ and concentrated under reduced pressure. The resulting residue was purified by flash chromatography (silica gel 230-400 mesh; 0-40% EtOAc/petroleum ether) to afford 220 mg (39%) of CIS-8-((cyclopropylmethyl)(methyl)amino)-1-(4-methoxybenzyl)-8-phenyl-3-(2-(trifluoromethyl)pyrimidin-5-yl)-1,3-diazaspiro[4.5]decan-2-one as an off white solid (TLC 50% EtOAc in petroleum ether, Rf: 0.65) and 230 mg of the unreacted starting material.

Step 4: CIS-8-((cyclopropylmethyl)(methyl)amino)-8-phenyl-3-(2-(trifluoromethyl)pyrimidin-5-yl)-1,3-diazaspiro[4.5]decan-2-one (SC_3132)

TFA (4.2 mL) was added drop wise to a solution of CIS-8-((cyclopropylmethyl)(methyl)amino)-1-(4-methoxybenzyl)-8-phenyl-3-(2-(trifluoromethyl)pyrimidin-5-yl)-1,3-diazaspiro[4.5]decan-2-one (210 mg, 0.363 mmol) in DCM (0.05 mL) at 0° C. under argon atmosphere. The reaction mixture was allowed to warm up to RT and stirred for 16h. The reaction progress was monitored by LCMS. The excess of TFA was evaporated under reduced pressure and the residual amount of TFA was removed as an azeotropic mixture with DCM (2×5 mL). The crude product was purified by preparative HPLC to yield 105 mg (63%) of CIS-8-((cyclopropylmethyl)(methyl)amino)-8-phenyl-3-(2-(trifluoromethyl)pyrimidin-5-yl)-1,3-diazaspiro[4.5]decan-2-one (SC_3132) as an off white solid (TLC system 50% EtOAc in pe ether, Rf: 0.35). ¹H NMR (DMSO-d6): δ 9.17 (s, 2H), 8.10 (br s, 1H), 7.35-7.33 (m, 4H), 7.25-7.22 (m, 1H), 3.72 (s, 2H), 2.43 (m, 2H), 2.13 (s, 3H), 1.97-1.82 (m, 6H), 1.49 (m, 2H), 0.75-0.71 (m, 1H), 0.41-0.39 (m, 2H), 0.06-0.01 (m, 2H). Mass: m/z=460.2 (M+H).

Synthesis of SC_3133:CIS-8-Dimethylamino-3-[2-(4-methyl-piperazine-1-carbonyl)-pyrimidin-5-yl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one

1-Methylpiperazine (2 equiv., 0.5 mmol, 55 μL) and [5-[8-(dimethylamino)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]pyrimidine-2-carbonyl]oxylithium (INT-990) (100 mg, 0.25 mmol) were suspended in DCM (1.6 mL), triethylamine (10 equiv., 2.5 mmol, 336 μL) and propylphosphonic anhydride (>50 wt. % solution in ethyl acetate) (2 equiv., 0.5 mmol, 297 μL) were sequentially added and the reaction mixture was stirred at RT for 2 h. The resulting mixture was quenched with 2M aq. NaOH (2 mL), organic phase was separated and aqueous phase was extracted with dichloromethane (3×10 mL). The combined organic extracts were dried over Na₂SO₄ and concentrated under reduced pressure. The residue (88 mg) was dissolved in 3 mL DCM and 6 mL pentane were slowly added. The resulting mixture was stirred for 30 min. The precipitate was filtered off and dried under reduced pressure to give 69 mg (58%) of CIS-8-dimethylamino-3-[2-(4-methyl-piperazine-1-carbonyl)-pyrimidin-5-yl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one (SC_3133). H NMR (600 MHz, DMSO) δ 9.03 (s, 2H), 7.87 (s, 1H), 7.42-7.34 (m, 5H), 7.28 (d, 1H), 3.69 (s, 2H), 3.62 (dd, 2H), 3.17-3.12 (m, 2H), 2.57-2.51 (m, 2H), 2.36 (t, 2H), 2.25-2.21 (m, 2H), 2.21 (s, 3H), 1.98-1.89 (m, 2H), 1.96 (s, 6H), 1.56-1.46 (m, 2H). Mass: m/z 478.29 (M+H).

Synthesis of SC_3146: CIS-5-(8-(dimethylamino)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)pyrimidine-2-carboxamide

Methyl CIS-5-(8-(dimethylamino)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)pyrimidine-2-carboxylate (INT-990) (100 mg, 0.244 mmol) was dissolved in 7N NH₃ in methanol (25 equiv. NH₃, 0.9 mL) in a microwave reactor vial. The reaction vessel was sealed, the reaction mixture was stirred for 5 days at RT and then concentrated under reduced pressure. The residue was purified by flash chromatography on neutral aluminum oxide (DCM/EtOH, gradient 90/10 to 74/26) to yield 38 mg (39%) of CIS-5-(8-(dimethylamino)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)pyrimidine-2-carboxamide (SC_3140). ¹H NMR (600 MHz, DMSO) δ 9.07 (s, 2H), 8.02 (d, 1H), 7.93 (s, 1H), 7.59-7.55 (m, 1H), 7.38 (d, 4H), 7.28 (ddd, 1H), 3.72 (s, 2H), 2.49-2.37 (m, 2H), 1.99-1.92 (m, 8H), 1.88-1.75 (m, 2H), 1.56-1.45 (m, 2H). Mass: m/z 395.22 (M+H)⁺.

Synthesis of SC_3146: methyl CIS-2-(4-(5-(8-(dimethylamino)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)pyrimidin-2-yl)piperazin-1-yl)acetate

CIS-8-(dimethylamino)-8-phenyl-3-(2-(piperazin-1-yl)pyrimidin-5-yl)-1,3-diazaspiro[4.5]decan-2-one (SC_3124) (200 mg, 0.46 mmol) was dissolved in dry acetonitrile (5 mL) under nitrogen atmosphere, KCO₃ (1.2 equiv., 0.55 mmol, 76 mg) and methyl-2-chloroacetate (1.5 equiv., 0.69 mmol, 0.06 mL) were sequentially added and the reaction mixture was stirred at reflux for 5 h. A new portion of methyl-2-chloroacetate (1.5 equiv., 0.69 mmol, 0.06 mL) was added and the reaction mixture was stirred at reflux overnight. The reaction mixture was concentrated under reduced pressure. The residue was suspended in DCM, the precipitate was filtered off and washed with DCM. The combined filtrate was concentrated under reduced pressure to give 106 mg of crude product. Flash chromatography on silica gel (eluent DCM/EtOH gradient 98/2 to 96/4) yielded 168 mg (72%) of methyl CIS-2-(4-(5-(8-(dimethylamino)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)pyrimidin-2-yl)piperazin-1-yl)acetate (SC_3146). ¹H NMR (600 MHz, DMSO) δ 8.54 (s, 2H), 7.42 (s, 1H), 7.37 (m, 4H), 7.27 (m, 1H), 3.63 (t, 7H), 3.52 (s, 2H), 3.27 (s, 2H), 2.54 (t, 4H), 2.45-2.30 (m, 2H), 1.96 (s, 6H), 1.93-1.83 (m, 4H), 1.52-1.42 (m, 2H). Mass: m/z 508.4 (M+H)⁺.

Synthesis of SC_3162: CIS-8-(dimethylamino)-8-phenyl-3-(2-(pyridin-2-yl)pyrimidin-5-yl)-1,3-diazaspiro[4.5]decan-2-one

CIS-3-(2-chloropyrimidin-5-yl)-8-(dimethylamino)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one (INT-989) (200 mg, 0.52 mmol), tributyl(2-pyridyl)stannane (1.5 equiv., 0.78 mmol, 286 mg) and Pd(PPh₃)₄ (0.1 equiv., 0.052 mmol, 60 mg) were dissolved in degassed anhydrous DMF (150 equiv., 77.7 mmol, 6 mL) under nitrogen atmosphere. Cesium fluoride (2.2 equiv., 1.14 mmol, 173 mg) was added and the reaction mixture was stirred at 90° C. overnight. The resulting suspension was cooled down to RT, diluted with water (10 mL), extracted with ethylacetate (30 mL), then DCM (30 mL), the DCM phase was dried over MgSO₄ and concentrated under reduced pressure to give 320 mg of crude product. Flash chromatography on silica gel (eluent DCM/0.1N NH₃ in MeOH, gradient 95/5 to 70/30) yielded 72 mg (33%) of CIS-8-(dimethylamino)-8-phenyl-3-(2-(pyridin-2-yl)pyrimidin-5-yl)-1,3-diazaspiro[4.5]decan-2-one (SC_3162). ¹H NMR (600 MHz, DMSO) δ 9.13 (s, 2H), 8.71-8.67 (m, 1H), 8.30 (d, 1H), 7.92 (td, 1H), 7.86 (s, 1H), 7.46 (dd, 1H), 7.43-7.35 (m, 5H), 7.31-7.25 (m, 1H), 3.73 (s, 2H), 2.48-2.33 (m, 2H), 2.00-1.78 (m, 10H), 1.57-1.47 (m, 2H). Mass: m/z 429.2 (M+H)⁺.

Synthesis of SC_3169: CIS-2-(2-(8-(dimethylamino)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)phenoxy)acetic Acid

Step 1: CIS-2-(2-(8-(dimethylamino)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)phenoxy)acetonitrile

In analogy to the method described for SC_3103 CIS-8-(dimethylamino)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one (INT-976) was reacted with 2-(2-bromophenoxy)acetonitrile to be converted into CIS-2-(2-(8-(dimethylamino)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)phenoxy)acetonitrile.

Step 2: CIS-2-(2-(8-(dimethylamino)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)phenoxy)acetic Acid (SC_3169)

CIS-2-(2-(8-(dimethylamino)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)phenoxy)acetonitrile (134 mg, 0.331 mmol) was dissolved in conc. aq. HCl (1.4 mL, 50 equiv.). The reaction mixture was heated to 100° C. for 2 h and cooled down to RT. The precipitate was filtered off, washed with water (2×) and dried under reduced pressure to give 31 mg (22%) of CIS-2-(2-(8-(dimethylamino)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)phenoxy)acetic acid (SC_3169). ¹H NMR (600 MHz, DMSO) δ 7.75-7.71 (m, 1H), 7.59-7.48 (m, 4H), 7.27 (dd, 1H), 7.15 (ddd, 1H), 6.97-6.90 (m, 2H), 4.65 (s, 2H), 3.43 (s, 2H), 2.70 (d, 2H), 2.56 (s, 6H), 2.31 (t, 2H), 1.93-1.86 (m, 2H), 1.33-1.22 (m, 2H). Mass: m/z 424.2 (M+H)⁺.

Synthesis of SC_3173: CIS-8-(dimethylamino)-8-phenyl-3-(2-(piperazine-1-carbonyl)pyrimidin-5-yl)-1,3-diazaspiro[4.5]decan-2-one

Step 1: CIS-tert-butyl 4-(5-(8-(dimethylamino)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)pyrimidine-2-carbonyl)piperazine-1-carboxylate

In analogy to the method described for SC_3133 lithium CIS-5-(8-(dimethylamino)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)pyrimidine-2-carboxylate (INT-990) was reacted with 1-(tert-butoxycarbonyl)piperazine to be converted into CIS-tert-butyl 4-(5-(8-(dimethylamino)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)pyrimidine-2-carbonyl)piperazine-1-carboxylate.

Step 2: CIS-8-(dimethylamino)-8-phenyl-3-(2-(piperazine-1-carbonyl)pyrimidin-5-yl)-1,3-diazaspiro[4.5]decan-2-one (SC_3173)

CIS-tert-butyl 4-(5-(8-(dimethylamino)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)pyrimidine-2-carbonyl)piperazine-1-carboxylate (230 mg, 0.41 mmol) was dissolved in TFA (2.2 mL, 28.6 mmol, 70 equiv.). The reaction mixture was stirred at RT for 2.5 h and then concentrated under reduced pressure. The residue was dissolved in DCM and aq. sat Na₂CO₃ was added (until pH 10). The organic phase was separated and the aq. phase was extracted with DCM (2×). The combined organic extracts were dried over MgSO₄ and concentrated under reduced pressure. Recrystallization of the residue from DCM/pentane gave 105 mg (56%) of CIS-8-(dimethylamino)-8-phenyl-3-(2-(piperazine-1-carbonyl)pyrimidin-5-yl)-1,3-diazaspiro[4.5]decan-2-one (SC_3173). ¹H NMR (600 MHz, DMSO) δ 9.04 (s, 2H), 7.89 (s, 1H), 7.42-7.32 (m, 4H), 7.31-7.26 (m, 1H), 3.69 (s, 2H), 3.65 (t, 2H), 3.21 (t, 2H), 2.90 (t, 2H), 2.79-2.74 (m, 2H), 2.43 (s, 2H), 1.98 (s, 9H), 1.89-1.75 (m, 1H), 1.53-1.47 (m, 2H). Mass: m/z 464.3 (M+H)⁺.

Synthesis of SC_3182: CIS-8-(dimethylamino)-3-(2-(4-hydroxypiperidin-1-yl)pyrimidin-5-yl)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one

Et₃N (0.39 g, 3.89 mmol) was added to the solution of CIS-3-(2-chloropyrimidin-5-yl)-8-(dimethylamino)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one (INT-989) (0.5 g, 1.29 mmol) and piperidin-4-ol (0.32 g, 3.24 mmol) in DMF (10 mL) at RT. The reaction mixture was stirred at 130° C. for 16h, cooled down to RT and concentrated under reduced pressure. The residue was diluted with 10% aq. NaOH and the organic product was extracted with 1/9 v/v MeOH/DCM. The combined organic layer was dried over anhydrous Na₂SO₄ and concentrated in vacuo. The residue was purified by preparative TLC using 10% MeOH/DCM as eluent to afford 130 mg of CIS-8-(dimethylamino)-3-(2-(4-hydroxypiperidin-1-yl)pyrimidin-5-yl)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one (SC_3182) as an off-white solid (TLC system: 10% MeOH in DCM; Rf: 0.1). ¹H NMR (DMSO-d6): δ 8.50 (s, 2H), 7.39-7.26 (m, 6H), 4.68 (d, 1H), 4.19-4.16 (m, 2H), 3.69-3.67 (m, 1H), 3.51 (s, 2H), 3.14 (t, 2H), 2.33 (m, 2H), 1.94-1.71 (m, 12H), 1.45 (m, 2H), 1.30-1.23 (m, 2H). Mass: m/z 451.2 (M+H)⁺.

Synthesis of SC_3186: CIS-8-(dimethylamino)-3-(3-methylpyridin-2-yl)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one

Compound was synthesized within a parallel array. An argon-flushed dry reaction vessel equipped with a septum was loaded with the solutions of INT-976 (0.1 M, 1 mL) and 1-bromo-2-methylbenzene (0.15 M, 1 mL) in dioxane. To the resulting mixture Cs₂CO₃ (200 μmol), XantPhos (10 μmol) and Pd₂(dba)₃ (5 μmol) were added. The reaction vessel was flushed with argon once again, sealed and the reaction mixture was shaken at 100° C. overnight. The resulting mixture was cooled down to RT and the solvent was removed under reduced pressure. The residue was taken up in 3 mL dichloromethane and 3 mL water, the organic phase was separated, the aqueous phase was extracted with dichloromethane (2×3 mL). Combined organic phases were concentrated under reduced pressure. The residue was purified by HPLC to give CIS-8-(dimethylamino)-3-(3-methylpyridin-2-yl)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one (SC_3186). Mass: m/z 363.2 (M+H)⁺.

Synthesis of SC_3208: CIS-4-(5-(8-(dimethylamino)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)pyrimidin-2-yl)indolin-2-one

CIS-3-(2-chloropyrimidin-5-yl)-8-(dimethylamino)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one (INT-989) (150 mg, 0.38 mmol), Pd(t-Bu₃P)₂ (0.1 equiv., 0.02 mmol, 10 mg) and 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)indolin-2-one (2 equiv., 0.78 mmol, 201 mg) were dissolved in degassed anhydrous THF (80 equiv., 31 mmol, 2.5 mL) and IM aq. Na₂CO₃ (5.5 equiv., 2.14 mmol, 2.14 mL) was added. The resulting mixture was stirred at 60° C. for 8 h and then at RT overnight. The reaction mixture was diluted with water until precipitation occurred. The precipitate was filtered off, suspended in 30 mL DCM, filtered off again, washed with pentane (5 mL) and dried under reduced pressure to give 143 mg (76%) of CIS-4-(5-(8-(dimethylamino)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)pyrimidin-2-yl)indolin-2-one (SC_3208). ¹H NMR (600 MHz, DMSO) δ 10.45 (s, 1H), 9.10 (s, 2H), 7.87 (d, 1H), 7.84-7.80 (m, 1H), 7.39 (d, 5H), 7.29 (dt, 2H), 6.91 (d, 1H), 3.82 (s, 2H), 3.72 (s, 2H), 2.41 (d, 2H), 2.03-1.74 (m, 9H), 1.60-1.44 (m, 3H). Mass: m/z 484.26 (M+H)⁺.

Synthesis of SC_3221: CIS-8-(dimethylamino)-3-(2-((2-hydroxyethyl)amino)pyrimidin-5-yl)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one

Step 1: CIS-8-(dimethylamino)-3-(2-((2-methoxyethyl)amino)pyrimidin-5-yl)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one

In analogy to the method described for SC_3103 2-methoxyethanamine was reacted with CIS-3-(2-chloropyrimidin-5-yl)-8-(dimethylamino)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one (INT-989) to be converted into CIS-8-(dimethylamino)-3-(2-((2-methoxyethyl)amino)pyrimidin-5-yl)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one.

Step 2: CIS-8-(dimethylamino)-3-(2-((2-hydroxyethyl)amino)pyrimidin-5-yl)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one (SC_3221)

BBr₃ (IM in DCM) (2.2 mL, 2.22 mmol) was added to the solution of CIS-8-(dimethylamino)-3-(2-((2-methoxyethyl)amino)pyrimidin-5-yl)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one (0.55 g, 1.06 mmol) in DCM (20 mL) at −78° C. over 15 min. The reaction mixture was stirred at RT for 4 h, then quenched with water and concentrated under reduced pressure. The residue was purified by preparative reverse phase HPLC to afford 82 mg (19%) of CIS-8-(dimethylamino)-3-(2-((2-hydroxyethyl)amino)pyrimidin-5-yl)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one (SC_3221) (TLC system: 10% MeOH in DCM (Ammonia atmosphere); R_(f): 0.3). ¹H NMR (DMSO-d6): δ 8.41 (s, 2H), 7.39-7.24 (m, 6H), 6.70 (t, 1H), 4.64 (br, s, 1H), 3.50-3.45 (m, 4H), 3.28-3.25 (m, 2H), 2.37 (br m, 2H), 1.94-1.86 (m, 10H), 1.45 (m, 2H). Mass: m/z 411.2 (M+H)+

Synthesis of SC_3224: CIS-3-(2-(1H-indazol-1-yl)pyrimidin-5-yl)-8-(dimethylamino)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one

K₂CO₃ (0.53 g, 3.89 mmol) was added to the solution of CIS-3-(2-chloropyrimidin-5-yl)-8-(dimethylamino)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one (500 mg, 1.29 mmol) and 1H-indazole (306 mg, 2.59 mmol) in DMF (10 mL). The reaction mixture was stirred at 140° C. for 48h, cooled down to RT and concentrated under reduced pressure. The residue was diluted with DCM (50 mL), filtered through Celite and the filtrate was concentrated under reduced pressure. The residue was purified by flash chromatography using neutral alumina (0-10% MeOH/DCM) followed by reverse phase HPLC to afford 77 mg (13%) of CIS-3-(2-(1H-indazol-1-yl)pyrimidin-5-yl)-8-(dimethylamino)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one (SC_3224) as off-white solid (TLC system: 10% MeOH in DCM; Rf: 0.6). ¹H NMR (DMSO-d6): δ 9.10 (s, 2H), 8.57-8.55 (d, 1H), 8.41 (s, 1H), 7.89-7.87 (d, 1H), 7.82 (br s, 1H), 7.57-7.53 (t, 1H), 7.39-7.28 (m, 6H), 3.72 (s, 2H), 2.45 (m, 2H), 1.98-1.93 (m, 10H), 1.52 (m, 2H). Mass: m/z 468.2 (M+H)⁺.

Synthesis of SC_3235: CIS-methyl 2-(2-(8-(dimethylamino)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)phenoxy)acetate

CIS-2-(2-(8-(dimethylamino)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)phenoxy)acetic acid (120 mg, 0.28 mmol) was dissolved in methanol (1.4 mL, 125 equiv.) and thionyl chloride (4 equiv., 1.13 mmol, 83 μL) was added dropwise. The reaction mixture was stirred at RT overnight, diluted with aq. sat. NaHCO₃ and extracted with DCM (3×). The combined organic phases were dried over MgSO₄ and concentrated under reduced pressure. The residue (112 mg) was purified by flash chromatography on silica get (gradient DCM/MeOH 97/3 to 88/12) to give 92 mg (74%) of CIS-methyl 2-(2-(8-(dimethylamino)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)phenoxy)acetate (SC_3235). ¹H NMR (600 MHz, DMSO) δ 7.40-7.33 (m, 4H), 7.29 (dd, 1H), 7.28-7.24 (m, 1H), 7.13 (td, 1H), 6.99-6.91 (m, 2H), 4.76 (s, 2H), 3.67 (s, 3H), 3.55 (s, 2H), 2.45-2.26 (m, 2H), 2.07 (s, 2H), 1.98 (s, 6H), 1.94-1.75 (m, 4H), 1.52-1.45 (m, 2H). Mass: m/z 438.2 (M+H)⁺.

Synthesis of SC_3238: CIS-2-(5-(8-(dimethylamino)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)pyrimidin-2-yl)benzonitrile

CIS-3-(2-chloropyrimidin-5-yl)-8-(dimethylamino)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one (INT-989) (240 mg, 0.56 mmol), [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) complex with dichloromethane (0.05 equiv., 0.028 mmol, 23 mg) and (2-cyanophenyl)boronic acid (1.125 equiv., 0.63 mmol, 92 mg) were dissolved in degassed 1,2-dimethoxyethane (100 equiv., 56 mmol, 5.8 mL) and Cs₂CO₃ (3.3 equiv., 1.84 mmol, 600 mg) in water (175 equiv., 98 mmol, 1.8 mL) was added. The resulting clear reaction mixture was stirred 3 days at 60° C. The reaction mixture was diluted with water (15 mL) and extracted with EtOAc (2×15 mL). Combined organic phases were dried over MgSO₄ and concentrated under reduced pressure. The residue (355 mg) was purified by flash chromatography on silica get (gradient DCM/MeOH 95/5 to 70/30) to give 60 mg of product, which was further purified by HPLC to give 15.4 mg (6%) of CIS-2-(5-(8-(dimethylamino)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)pyrimidin-2-yl)benzonitrile (SC_3238). ¹H NMR (600 MHz, DMSO) δ 9.17 (s, 2H), 8.27 (dd, 1H), 7.94 (dd, 1H), 7.81 (td, 1H), 7.65 (td, 1H), 7.42-7.35 (m, 5H), 7.28 (ddt, 1H), 3.75 (s, 2H), 2.49-2.34 (m, 1H), 2.00-1.76 (m, 11H), 1.55-1.51 (m, 2H). Mass: m/z 453.24 (M+H)⁺.

Synthesis of SC_3239: CIS-3-(2-aminopyrimidin-5-yl)-8-(dimethylamino)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one

Microwave reactor vial was loaded with CIS-3-(2-chloropyrimidin-5-yl)-8-(dimethylamino)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one (INT-989) (250 mg, 0.65 mmol), flushed with nitrogen, 7N solution of NH₃ in methanol (108 equiv., 70 mmol, 10 mL) and dioxane (37 equiv., 24 mmol, 2 mL) were added, the vial was sealed and the reaction mixture was stirred at 115° C. for 12 h in the microwave reactor. The reaction mixture was then cooled down to 4° C. overnight. The precipitate formed was filtered off, washed with DCM (small amount), water (2×), ether (2×) and dried under reduced pressure to give 180 mg (76%) of CIS-3-(2-aminopyrimidin-5-yl)-8-(dimethylamino)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one (SC_3239) as an off-white solid. ¹H NMR (600 MHz, DMSO) δ 8.39 (s, 2H), 7.40-7.32 (m, 5H), 7.26 (tt, 1H), 6.25 (s, 2H), 3.51 (s, 2H), 2.37 (s, 2H), 2.07 (s, 2H), 1.96 (s, 6H), 1.94-1.68 (m, 4H), 1.47 (d, 2H). Mass: m/z 367.23 (M+H)⁺.

Synthesis of SC_3240: CIS-N-(5-(8-(dimethylamino)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)pyrimidin-2-yl)cyclopropanecarboxamide

CIS-3-(2-aminopyrimidin-5-yl)-8-(dimethylamino)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one (SC_3239) (50 mg, 0.14 mmol) and 4-dimethylaminopyridine (1.3 equiv., 0.18 mmol, 22 mg) were dissolved in dry pyridine (200 equiv., 27 mmol, 2.2 mL) under nitrogen atmosphere. Cyclopropancarbonyl chloride (1.3 equiv., 0.18 mmol, 16 μL) was added in one portion and the reaction mixture was stirred at RT for 3 h. Additional portion of cyclopropancarbonyl chloride (3 equiv., 0.42 mmol, 37 μL) was added and the reaction mixture was stirred at 90° C. for 1 h. The reaction mixture was diluted with water (5 mL) and aq. sat. NaHCO₃ (5 mL), extracted with DCM (3×10 mL), organic phases were washed with brine, dried over Na₂SO₄ and the solvent was removed under reduced pressure. The residue was suspended thoroughly in 3 mL DCM, the precipitate was filtered off, washed with ether and dried under reduced pressure to give 47 mg (79%) of CIS-N-(5-(8-(dimethylamino)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)pyrimidin-2-yl)cyclopropanecarboxamide (SC_3240) as a white solid. ¹H NMR (600 MHz, DMSO) δ 10.66 (s, 1H), 8.81 (s, 2H), 7.67 (s, 1H), 7.41-7.33 (m, 4H), 7.31-7.21 (m, 1H), 3.62 (s, 2H), 2.45-2.32 (m, 2H), 2.01 (td, 1H), 1.96 (s, 6H), 1.93-1.78 (m, 3H), 1.52-1.47 (m, 2H), 0.82-0.72 (m, 4H). Mass: m/z 435.3 (M+H)⁺.

Synthesis of SC_3242: CIS-8-(dimethylamino)-8-phenyl-3-(6-(piperazin-1-yl)pyridin-3-yl)-1,3-diazaspiro[4.5]decan-2-one

Step 1: 4-(5-bromopyrimidin-2-yl)piperazine

In analogy to the method described for SC_3097 step 1 5-bromo-2-chloro-pyridine was reacted with piperazine to be converted into 4-(5-bromopyrimidin-2-yl)piperazine.

Step 2: CIS-8-(dimethylamino)-8-phenyl-3-(6-(piperazin-1-yl)pyridin-3-yl)-1,3-diazaspiro [4.5]decan-2-one (SC_3242)

CIS-8-(dimethylamino)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one (INT-976) (80 mg, 0.29 mmol), 4-(5-bromopyrimidin-2-yl)piperazine (2 equiv., 0.56 mmol, 142 mg) and potassium phosphate (4 equiv., 1.17 mmol, 248 mg) were suspended in N,N′-dimethylethylenediamine (18 equiv., 5.27 mmol, 0.6 mL) under nitrogen atmosphere. The reaction mixture was stirred at 80° C. for 2 h, diluted with water (10 mL) and extracted with DCM (3×15 mL). The combined organic phases contained a precipitate which was filtered off, washed with isopropanol and dried under reduced pressure to give 79 mg (62%) of CIS-8-(dimethyl-amino)-8-phenyl-3-(6-(piperazin-1-yl)pyridin-3-yl)-1,3-diazaspiro [4.5]decan-2-one (SC_3242). ¹H NMR (600 MHz, DMSO) δ 8.15 (d, 1H), 7.85 (dd, 1H), 7.41-7.33 (m, 4H), 7.32-7.23 (m, 2H), 6.74 (d, 1H), 3.51 (s, 2H), 3.30-3.25 (m, 4H), 2.78-2.73 (m, 4H), 2.43-2.31 (m, 2H), 1.96 (s, 6H), 1.93-1.79 (m, 4H), 1.50-1.42 (m, 2H). Mass: m/z 435.3 (M+H)⁺.

Synthesis of SC_3275: CIS-8-(ethylamino)-1-((1-hydroxycyclobutyl)methyl)-8-phenyl-3-(2-(trifluoromethyl)pyrimidin-5-yl)-1,3-diazaspiro[4.5]decan-2-one

CIS-8-amino-1-((1-hydroxycyclobutyl)methyl)-8-phenyl-3-(2-(trifluoromethyl)pyrimidin-5-yl)-1,3-diazaspiro[4.5]decan-2-one (70 mg, 0.15 mmol) was dissolved in anhydrous DCM (3.8 mL) under nitrogen atmosphere. Acetic acid (0.1 equiv., 0.015 mmol, 0.8 μL) and acetaldehyde (1.1 equiv., 0.16 mmol, 9 μL) were sequentially added and the resulting mixture was stirred at RT for 1 h. Sodium triacetoxyborohydride (2 equiv., 0.29 mmol, 62 mg) was added and the reaction mixture was stirred at RT overnight and then at 50° C. for 5 h. Additional amounts of acetaldehyde (1.1 equiv., 0.16 mmol, 9 μL) and sodium triacetoxyborohydride (2 equiv., 0.29 mmol, 62 mg) were added and the reaction mixture was stirred further 24 h at 50° C. The resulting mixture was cooled down to RT, quenched with aq. sat. NaHCO₃ until pH>7, diluted with water and extracted with DCM (3×). The combined organic layers were dried over Na₂SO₄ and concentrated under reduced pressure. The residue (70 mg) was purified by flash chromatography on silica gel (DCM/EtOH gradient 99/1 to 95/5) to yield 43 mg (58%) of CIS-8-(ethylamino)-1-((1-hydroxycyclobutyl)methyl)-8-phenyl-3-(2-(trifluoromethyl)pyrimidin-5-yl)-1,3-diazaspiro[4.5]decan-2-one (SC_3275). ¹H NMR (600 MHz, DMSO) δ 9.26 (s, 2H), 7.55-7.49 (m, 2H), 7.33 (t, 2H), 7.21 (d, 1H), 3.92 (s, 2H), 2.38 (td, 2H), 2.17-2.06 (m, 3H), 2.00-1.87 (m, 4H), 1.81 (td, 2H), 1.72-1.64 (m, 1H), 1.60-1.50 (m, 1H), 1.49-1.43 (m, 2H), 0.99 (t, 3H). Mass: m/z 504.3 (M+H)⁺

Synthesis of SC_3292 and SC_3293: enantiomer 1 and enantiomer 2 of CIS-8-(methyl((tetrahydrofuran-3-yl)methyl)amino)-8-phenyl-3-(2-(trifluoromethyl)pyrimidin-5-yl)-1,3-diazaspiro[4.5]decan-2-one

Cs₂CO₃ (0.85 g, 2.61 mmol) was added to an argon purged solution of CIS-8-(methyl((tetrahydrofuran-3-yl)methyl)amino)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one (INT-1026) (0.3 g, 0.87 mmol), Xanthphos (45 mg, 0.087 mmol), Pd₂(dba)₃ (80 mg, 0.087 mmol) and 5-bromo-2-(trifluoromethyl)pyrimidine (0.29 g, 1.30 mmol) in 1,4-dioxane (15 mL). The mixture was purged with argon for 5 min and stirred at 90° C. for 16 h. The reaction mixture was cooled to RT, diluted with EtOAc (20 mL), filtered through Celite and the filtrate was concentrated under reduced pressure. The crude product was purified by flash chromatography (silica gel 230-400 mesh; 3% MeOH in DCM) to get the compound which was further purified by reverse phase preparative HPLC to afford 0.1 g (23%) of CIS-8-(methyl((tetrahydrofuran-3-yl)methyl)amino)-8-phenyl-3-(2-(trifluoromethyl)pyrimidin-5-yl)-1,3-diazaspiro[4.5]decan-2-one (TLC system: 10% MeOH in DCM; Rf: 0.4) as a mixture of enantiomers. Reverse phase preparative HPLC conditions: mobile phase: 10 mM ammonium bicarbonate in H₂O/acetonitrile; column: X-BRIDGE-C18 (150*19), 5 μm; mobile phase gradient (min/% B): 0/30, 8/82, 8.1/100, 10/100, 10.1/30, 12/30; flow rate: 19 ml/min; diluent: mobile phase+THF. Enantiomeric mixture of CIS-8-(methyl((tetrahydrofuran-3-yl)methyl)amino)-8-phenyl-3-(2-(trifluoromethyl)pyrimidin-5-yl)-1,3-diazaspiro[4.5]decan-2-one (100 mg) was separated by chiral SFC to afford 35 mg of enantiomer 1 (SC-3292) and 40 mg of enantiomer 2 (SC-3293) as off-white solids. Preparative SFC conditions: column: Chiralpak IA (250×30) mm, 5 μm; % CO₂: 50.0%; % co-solvent: 50.0% (100% Methanol); total flow: 70.0 g/min; back pressure: 100.0 bar; UV: 256 nm; stack time: 13.5 min; load/inj.: 9.5 mg; no. of injections: 11. SC-3292: ¹H NMR (DMSO-d6): δ 9.15 (s, 2H), 8.23 (broad s, 1H), 7.37-7.25 (m, 5H), 3.68-3.58 (m, 5H), 3.37-3.36 (m, 1H), 2.32 (m, 3H), 2.13-1.89 (m, 10H), 1.47 (m, 3H). SC-3293: ¹H NMR (DMSO-d6): δ 9.15 (s, 2H), 8.23 (broad s, 1H), 7.37-7.36 (m, 4H), 7.26-7.24 (m, 1H), 3.68-3.56 (m, 5H), 3.37-3.36 (m, 1H), 2.31-2.28 (m, 3H), 2.13-1.86 (m, 10H), 1.48 (m, 3H). Mass: m/z 490.3 (M+H)⁺.

Synthesis of SC_3313: CIS-3-(2-(4-cyclopropyl-1H-1,2,3-triazol-1-yl)pyrimidin-5-yl)-8-(dimethylamino)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one

Step 1: 5-bromo-2-(4-cyclopropyl-1H-1,2,3-triazol-1-yl)pyrimidine

2-Azido-5-bromo-pyrimidine (400 mg, 1.94 mmol) and ethynylcyclopropane (1.3 equiv., 2.522 mmol, 0.21 mL) were dissolved in tert-butanol (5 mL). The solutions of sodium ascorbate (0.1 equiv., 0.194 mmol, 38 mg) in water (2.5 mL) and copper(II) sulfate pentahydrate (0.1 equiv., 0.194 mmol, 48 mg) in water (2.5 mL) were sequentially added. The reaction mixture was stirred under ambient conditions for 18 h, then diluted with 20 mL 1M aq. NH₄OH and extracted with EtOAc (3×30 mL). The combined organic extracts were washed with brine, dried over Na₂SO₄ and concentrated under reduced pressure. Crude product (510 mg) was purified by flash chromatography on silica gel (DCM/EtOH 99/1) to yield 143 mg of 5-bromo-2-(4-cyclopropyl-1H-1,2,3-triazol-1-yl)pyrimidine as a white solid. Mass: m/z 266.0 (M+H)⁺.

Step 2: CIS-3-(2-(4-cyclopropyl-1H-1,2,3-triazol-1-yl)pyrimidin-5-yl)-8-(dimethylamino)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one (SC_3313)

In analogy to the method described for SC_3103 CIS-8-(dimethylamino)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one (INT-976) was reacted with 5-bromo-2-(4-cyclopropyl-1H-1,2,3-triazol-1-yl)pyrimidine to be converted into CIS-3-(2-(4-cyclopropyl-1H-1,2,3-triazol-1-yl)pyrimidin-5-yl)-8-(dimethylamino)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one (SC_3313). ¹H NMR (600 MHz, DMSO) δ 9.09 (d, 2H), 8.50 (d, 1H), 7.91 (s, 1H), 7.42-7.34 (m, 2H), 7.38 (s, 3H), 7.31-7.25 (m, 1H), 3.72 (s, 2H), 2.48-2.31 (m, 2H), 2.10-2.01 (m, 1H), 1.99-1.77 (m, 10H), 1.58-1.46 (m, 2H), 1.00-0.91 (m, 2H), 0.84 (tt, 2H). Mass: m/z 459.3 (M+H)⁺.

Synthesis of SC_3319: CIS-8-(methyl((tetrahydrofuran-3-yl)methyl)amino)-8-phenyl-3-(2-(trifluoromethyl)pyrimidin-5-yl)-1,3-diazaspiro[4.5]decan-2-one

Cs₂CO₃ (145 mg, 0.45 mmol, 2 equiv.), CIS-8-(dimethylamino)-8-(3-fluorophenyl)-1,3-diazaspiro[4.5]decan-2-one (INT-1024) (65 mg, 0.223 mmol, 1 equiv.), Xanthphos (19 mg, 0.033 mmol, 0.15 equiv.), Pd₂(dba)₃ (10 mg, 0.011 mmol, 0.05 equiv.) and 5-bromo-1-methyl-3-(trifluoromethyl)pyrazole (102 mg, 0.446 mmol, 2 equiv.) were loaded into a microwave reactor vial (2-5 mL), the vial was sealed and flushed with nitrogen (3×). 1,4-Dioxane (1.5 mL) was added via syringe and the reaction mixture was stirred at 110° C. in the microwave reactor for 10 h. The resulting mixture was cooled down to RT, solution of Xanthphos (19 mg, 0.033 mmol, 0.15 equiv.) and Pd₂(dba)₃ (10 mg, 0.011 mmol, 0.05 equiv.) in 1,4 dioxane (1 mL) was added, and the reaction mixture was stirred at 130° C. in the microwave reactor for further 10 h. The resulting suspension was cooled to RT, quenched with water and extracted with DCM (3×). The combined organic layer was dried over Na₂SO₄ and concentrated under reduced pressure. The resulting residue was purified by flash chromatography (gradient 0% to 16% MeOH in DCM) to yield 41 mg (42%) of CIS-8-(methyl((tetrahydrofuran-3-yl)methyl)amino)-8-phenyl-3-(2-(trifluoromethyl)pyrimidin-5-yl)-1,3-diazaspiro[4.5]decan-2-one (SC_3319). ¹H NMR (600 MHz, DMSO) δ 7.71 (s, 1H), 7.41 (q, 1H), 7.21-7.12 (m, 2H), 7.09 (td, 1H), 6.63 (s, 1H), 3.75 (s, 2H), 3.55 (s, 2H), 2.42-2.27 (m, 2H), 1.99-1.89 (m, 8H), 1.88-1.73 (m, 2H), 1.56-1.49 (m, 2H). Mass: m/z 440.2 (M+H)⁺.

Synthesis of SC_3340: CIS-2-(3-(8-(dimethylamino)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)pyridin-4-yl)acetamide

Step 1: CIS-2-(3-(8-(dimethylamino)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)pyridin-4-yl)acetonitrile

In analogy to the method described for SC_3097 step 2 CIS-8-(dimethylamino)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one (INT-976) was reacted with (3-bromo-pyridin-4-yl)-acetonitrile to be converted into CIS-2-(3-(8-(dimethylamino)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)pyridin-4-yl)acetonitrile.

Step 2: CIS-2-(3-(8-(dimethylamino)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)pyridin-4-yl)acetamide (SC_3340)

To a solution of CIS-2-(3-(8-(dimethylamino)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)pyridin-4-yl)acetonitrile (600 mg, 1.54 mmol, 1.0 equiv.) in EtOH (50 ml) was added NaOH (247 mg, 6.16 mmol, 4.0 equiv.). The reaction mixture was stirred at reflux for 16 h and then concentrated under reduced pressure. The resulting residue was purified by column chromatography (neutral alumina; 4% MeOH in DCM) and finally by preparative HPLC (column: Gemini NX-C₁₈ (50×4.6), 3 μm, diluent: DMSO, mobile phase: gradient 0.05% HCOOH in water/ACN flow rate: 1 ml/min) to yield CIS-2-(3-(8-(dimethylamino)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)pyridin-4-yl)acetamide (SC_3340) (40 mg, 0,098 mmol, 4% yield after two steps) as an off white solid. ¹HNMR (DMSO, 400 MHz) δ 8.40 (s, 1H), 8.32 (d, 1H, J=4.92 Hz), 7.49 (s, 1H), 7.36-7.24 (m, 7H), 6.99 (s, 1H), 3.49-3.46 (m, 4H), 2.32 (bs, 2H), 1.94-1.77 (m, 10H), 1.52 (bs, 2H). Mass: m/z 408.2 (M+H)⁺.

Synthesis of SC_3352: CIS-8-(dimethylamino)-3-(2-hydroxybenzo[d]oxazol-7-yl)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one

Step 1: CIS-7-(8-(dimethylamino)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)-3-((2-(trimethylsilyl)ethoxy)methyl)benzo[d]oxazol-2(3H)-one

In analogy to the method described for SC_3103 CIS-8-(dimethylamino)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one (INT-976) was reacted with 7-bromo-3-(2-trimethylsilanyl-ethoxymethyl)-3H-benzooxazol-2-one (prepared from 7-bromobenzo[d]oxazol-2(3H)-one and trimethylsilylethoxymethylchloride following a standard procedure) to be converted into CIS-7-(8-(dimethylamino)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)-3-((2-(trimethylsilyl)ethoxy)methyl)benzo[d]oxazol-2(3H)-one. Mass: m/z 537.2 (M+H)⁺.

Step 2: CIS-8-(dimethylamino)-3-(2-hydroxybenzo[d]oxazol-7-yl)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one (SC_3352)

To a solution of CIS-7-[8-dimethylamino-2-oxo-8-phenyl-1-(2-trimethylsilanyl-ethoxymethyl)-1,3-diaza-spiro[4.5]dec-3-yl]-3H-benzooxazol-2-one (350 mg, 0.65 mmol, 1.0 eq) in 1,4-dioxane (2 mL) was added 4M HCl in dioxane (6 mL) dropwise at 0° C. The reaction mixture was stirred at RT for 48 h and then concentrated under reduced pressure. The residue was taken in DCM (200 mL) and washed with sat. aq. NaHCO₃ (100 mL). Organic layer was dried over Na₂SO₄ and concentrated under reduced pressure to get the crude product which was purified by column chromatography (neutral alumina; 2% MeOH/DCM) to yield CIS-7-(8-dimethylamino-2-oxo-8-phenyl-1,3-diaza-spiro[4.5]dec-3-yl)-3H-benzooxazol-2-one (SC_3352) (85 mg, 0.21 mmol, 32%) as an off white solid. ¹HNMR (DMSO-d6, 400 MHz at 100° C.), δ (ppm)=11.19 (bs, 1H), 7.37-7.23 (m, 6H), 7.14 (s, 1H), 7.04 (t, 1H, J=8.06), 6.76 (d, 1H, J=7.68 Hz), 3.69 (s, 2H), 2.38-2.26 (m, 2H), 2.08-1.76 (m, 10H), 1.56-1.51 (m, 2H). Mass: m/z 407.1 (M+H)⁺.

Synthesis of SC_3354: CIS-4-(5-(8-(dimethylamino)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)pyrimidin-2-yl)benzamide Trifluoroacetate Salt

3-(2-chloropyrimidin-5-yl)-8-(dimethylamino)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one (INT 989) (200 mg, 0.52 mmol, 1 equiv.), 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide (129 mg, 0.52 mmol, 1 equiv.), Pd₂(dba)₃ (95 mg, 0.10 mmol, 0.2 equiv.), 2-dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl (X-Phos) (99 mg, 0.21 mmol, 0.4 equiv.) were loaded into microwave reactor vessel and flushed with nitrogen (2×). Anhydrous 1,4-dioxane (9 mL) and sodium carbonate (213 mg, 2.07 mmol, 4 equiv.) were sequentially added. The reaction mixture was stirred 8 h at 120° C. in the microwave reactor and then concentrated under reduced pressure. The residue was suspended in EtOAc/water (1/1, v/v) and filtered through a glass filter. The solid residue was dissolved in MeOH/DCM/TFA, filtered through Celite pad and the filtrate was concentrated under reduced pressure to give 75 mg (25%) of CIS-4-(5-(8-(dimethylamino)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)pyrimidin-2-yl)benzamide trifluoroacetate salt (SC_3354). ¹H NMR (600 MHz, DMSO) δ 9.05 (s, 2H), 8.42 (s, 1H), 8.34 (d, 2H), 8.03 (s, 1H), 7.98 (d, 2H), 7.74-7.65 (m, 2H), 7.58 (t, 2H), 7.56-7.52 (m, 1H), 7.40 (s, 1H), 3.58 (s, 2H), 2.70 (d, 2H), 2.60 (s, 6H), 2.25 (t, 2H), 1.91 (d, 2H), 1.39 (t, 2H). Mass: m/z 471.3 (M+H)⁺.

Synthesis of SC_3357: CIS-8-(dimethylamino)-3-(1H-indol-3-yl)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one

Step 1: CIS-8-(dimethylamino)-8-phenyl-3-(1-tosyl-1H-indol-3-yl)-1,3 diazaspiro[4.5]decan-2-one

In analogy to the method described for SC_3103 CIS-8-(dimethylamino)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one (INT-976) was reacted with 3-bromo-1-(toluene-4-sulfonyl)-1H-indole to be converted into CIS-8-(dimethylamino)-8-phenyl-3-(1-tosyl-1H-indol-3-yl)-1,3-diazaspiro[4.5]decan-2-one. Mass: m/z 543.1 (M+H)⁺.

Step 2: CIS-8-(dimethylamino)-3-(1H-indol-3-yl)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one (SC_3357)

To a solution of 8-dimethylamino-8-phenyl-3-[1-(toluene-4-sulfonyl)-1H-indol-3-yl]-1,3-diaza-spiro[4.5]decan-2-one (275 mg, 0.51 mmol, 1.0 eq.) in EtOH (24 mL) was added ION aq. NaOH (1.2 mL) at RT. The reaction mixture was heated to reflux for 1.5 h, then concentrated, diluted with water (50 mL) and extracted with EtOAc (150 mL). Organic layer was dried over Na₂SO₄ and concentrated under reduced pressure. The residue was purified by column chromatography (neutral alumina; 2% MeOH/DCM) to afford CIS-8-dimethylamino-3-(1H-indol-3-yl)-8-phenyl-1,3-diaza-spiro[4.5]decan-2-one (SC_3357) (130 mg, 0.33 mmol, 65%) as light brown solid. ¹H NMR (DMSO-d6, 400 MHz at 100° C.), δ (ppm)=10.55 (bs, 1H), 7.62-7.60 (d, 1H, J=7.96 Hz), 7.37-7.23 (m, 7H), 7.04 (t, 1H, J=7.48 Hz), 6.92 (t, 1H, J=7.44 Hz), 6.71 (bs, 1H), 3.61 (s, 2H), 2.38-2.33 (m, 2H), 2.04-1.82 (m, 10H), 1.59-1.54 (m, 2H). Mass: m/z 389.3 (M+H)⁺.

Synthesis of SC_3379: CIS-3-(1-acetyl-1H-indol-3-yl)-8-(dimethylamino)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one

To a solution of 8-dimethylamino-3-(1H-indol-3-yl)-8-phenyl-1,3-diaza-spiro[4.5]decan-2-one (SC_3357) (150 mg, 0.38 mmol, 1.0 eq.) in DCM (6 mL) were added NaOH (39 mg, 0.96 mmol, 2.5 eq.) and Bu₄NHSO₄ (129 mg, 0.38 mmol, 1.0 eq.) at 0° C. and the reaction mixture was stirred for 30 min followed by addition of acetyl chloride (54 μl, 0.76 mmol, 2.0 eq.). The reaction mixture was stirred at RT for 16 h, then diluted with DCM (150 ml) and washed with water (50 mL) and brine (50 mL). Organic layer was dried over Na₂SO₄ and concentrated under reduced pressure. The residue was purified by column chromatography (neutral alumina; 1% MeOH/DCM) followed by prep HPLC to afford 3-(1-acetyl-H-indol-3-yl)-8-dimethylamino-8-phenyl-1,3-diaza-spiro[4.5]decan-2-one (SC_3379) as off white solid. Note: Two batches of same reactions were done and yield was calculated accordingly. Yield: 13% (45 mg, 0.1 mmol). 1HNMR (DMSO-d6, 400 MHz at 100° C.), δ (ppm)=8.34-8.32 (d, 1H, J=7.88 Hz), 7.90 (d, 1H, J=7.36 Hz), 7.67 (s, 1H), 7.37-7.10 (m, 8H), 3.71 (s, 2H), 2.57 (s, 3H), 2.38-2.32 (m, 2H), 2.04-1.88 (m, 10H), 1.61-1.59 (m, 2H). Mass: m/z 431.2 (M+H)⁺.

Synthesis of SC_3388: CIS-8-(dimethylamino)-8-(3-hydroxyphenyl)-3-(4-methyl-6-(trifluoromethyl)pyridin-3-yl)-1,3-diazaspiro[4.5]decan-2-one

CIS-8-(dimethylamino)-8-(3-methoxyphenyl)-3-[4-methyl-6-(trifluoromethyl)-3-pyridyl]-1,3-diazaspiro[4.5]decan-2-one (SC_3368) (42 mg, 0.091 mmol) was dissolved in DCM (2 mL) and the solution was cooled to 0° C. Boron tribromide (1M sol. in DCM, 4 equiv., 0.36 mmol, 0.36 mL) was added in one portion. The reaction mixture was allowed to stir at RT overnight, then quenched with methanol and diluted with water. The resulting mixture was extracted with DCM (2×), the combined organic phases were dried over Na₂SO₄ and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel (eluent gradient DCM/EtOH) to yield 16 mg (39%) of CIS-8-(dimethylamino)-8-(3-hydroxyphenyl)-3-(4-methyl-6-(trifluoromethyl)pyridin-3-yl)-1,3-diazaspiro[4.5]decan-2-one (SC_3388). ¹H NMR (600 MHz, DMSO) δ 8.57 (s, 1H), 7.80 (s, 1H), 7.52 (s, 1H), 7.14 (t, 1H), 6.77 (d, 1H), 6.74 (s, 1H), 6.66 (dd, 1H), 3.61 (s, 2H), 2.32 (s, 3H), 2.31-2.19 (m, 2H), 2.01-1.89 (m, 8H), 1.88-1.70 (m, 2H), 1.54 (t, 2H). Mass: m/z 449.2 (M+H)⁺.

Synthesis of SC_3396: CIS-4-(8-(dimethylamino)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)indolin-2-one

Step 1: CIS-4-(8-(dimethylamino)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)-1-(4-methoxybenzyl)indoline-2,3-dione

In analogy to the method described for SC_3242 CIS-8-(dimethylamino)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one (INT-976) was reacted with 4-bromo-1-(4-methoxy-benzyl)-1H-indole-2,3-dione to be converted into CIS-4-(8-(dimethylamino)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)-1-(4-methoxybenzyl)indoline-2,3-dione. Mass: m/z 539.2 (M+H)⁺.

Step 2: CIS-4-(8-(dimethylamino)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)-1-(4-methoxybenzyl)indolin-2-one

To a solution of CIS-4-(8-dimethylamino-2-oxo-8-phenyl-1,3-diaza-spiro[4.5]dec-3-yl)-1-(4-methoxy-benzyl)-1H-indole-2,3-dione (600 mg, 1.11 mmol, 1.0 eq) in EtOH (9 mL) was added hydrazine hydrate (9 mL) at RT. The reaction mixture was stirred at reflux for 16 h, then concentrated, diluted with water (50 mL) and extracted with EtOAc (200 mL). Organic layer was dried over Na₂SO₄, filtered and concentrated under reduced pressure. The resulting residue was purified by column chromatography (neutral alumina, 0.5% MeOH/DCM) to afford 8-dimethylamino-3-[I-(4-methoxy-benzyl)-2-oxo-2,3-dihydro-1H-indol-4-yl]-8-phenyl-1,3-diaza-spiro[4.5]decan-2-one (275 mg, 0.52 mmol, 47%) as a brown solid. Mass: m/z 525.2 (M+H)*.

Step 3: CIS-4-(8-(dimethylamino)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)indolin-2-one (SC_3396)

A solution of CIS-8-dimethylamino-3-[1-(4-methoxy-benzyl)-2-oxo-2,3-dihydro-1H-indol-4-yl]-8-phenyl-1,3-diaza-spiro[4.5]decan-2-one (275 mg, 0.52 mmol, 1.0 eq.) in TFA (4 mL) was stirred at 90° C. in a sealed tube for 16 h. The reaction mixture was cooled to RT, concentrated under reduced pressure, diluted with water (50 mL), basified with sat. aq. NaHCO₃ and extracted with EtOAc (200 mL). The organic phase was washed with brine (50 mL), dried over Na₂SO₄, filtered and concentrated under reduced pressure. The resulting residue was purified by column chromatography (neutral alumina, 5% MeOH in DCM) to afford CIS-8-dimethylamino-3-(2-oxo-2,3-dihydro-1H-indol-4-yl)-8-phenyl-1,3-diaza-spiro[4.5]decan-2-one (SC_3396) (60 mg, 0.14 mmol, 28%) as an off-white solid. ¹H NMR (DMSO-d6, 400 MHz, 100° C.): δ (ppm)=9.98 (bs, 1H), 7.36-7.22 (m, 5H), 7.09 (t, 1H, J=7.94 Hz), 6.95-6.88 (m, 2H), 6.59 (d, 1H, J=7.52 Hz), 3.57 (s, 2H), 3.49 (s, 2H), 2.36-2.31 (m, 2H), 2.03 (s, 6H), 1.97-1.85 (m, 4H), 1.55-1.51 (m, 2H). Mass: m/z 405.3 (M+H)⁺.

The following compounds were prepared in analog and by combining previously described methods:

in analogy m/z Example Chemical Name Reactant I Reactant II to method [M + H]⁺ SC_3001 cis-5-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8- INT-987 5-bromopyrimidine-2- SC-3022 445.3 phenyl-1,3-diazaspiro[4.5]decan-3-yl]-pyrimidine-2- carbonitrile carbonitrile SC_3002 cis-5-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8- INT-987 5-bromopyrazine-2- SC-3022 445.3 phenyl-1,3-diazaspiro[4.5]decan-3-yl]-pyrazine-2-carbonitrile carbonitrile SC_3003 cis-5-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8- INT-987 5-bromo-4- phenyl-1,3-diazaspiro[4.5]decan-3-yl]-4-methoxy-pyrimidine- methoxypyrimidine-2- SC-3022 475.3 2-carbonitrile carbonitrile SC_3004 cis-5-[8-Dimethylamino-1-(2-methoxy-ethyl)-2-oxo-8-phenyl- INT-980 5-bromopyrimidine-2- SC-3022 435.2 1,3-diazaspiro[4.5]decan-3-yl]-pyrimidine-2-carbonitrile carbonitrile SC_3005 cis-5-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8- SC_3001 — SC_3016 463.3 phenyl-1,3-diazaspiro[4.5]decan-3-yl]-pyrimidine-2-carboxylic acid amide SC_3006 cis-5-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8- INT-987 5-bromo-2-(methylthio)- SC-3022 523.2 phenyl-1,3-diazaspiro[4.5]decan-3-yl]-2-methylsulfonyl- pyrimidine-4-carbonitrile (step 1); pyrimidine-4-carbonitrile SC_3008 (step 2) SC_3007 cis-5-[1-(2-Methoxy-ethyl)-8-methylamino-2-oxo-8-phenyl- SC_3004 — SC_3045 421.2 1,3-diazaspiro[4.5]decan-3-yl]-pyrimidine-2-carbonitrile SC_3008 cis-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8- INT-987 2-iodo-5- SC-3022 521.3 phenyl-1,3-diazaspiro[4.5]decan-3-yl]-5-methylsulfonyl- (methylthio)benzonitrile (step 1); benzonitrile (step 1) SC_3008 (step 2) SC_3009 cis-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8- SC_3090 — SC_3016 461.3 phenyl-1,3-diazaspiro[4.5]decan-3-yl]-benzamide SC_3010 cis-3-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8- SC_3072 — SC_3016 461.3 phenyl-1,3-diazaspiro[4.5]decan-3-yl]-benzamide SC_3011 cis-5-[8-Dimethylamino-1-[(1-hydroxy-cyclobutyl)-methyl]-2- SC_3013 — SC_3016 479.3 oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-pyrimidine-2- carboxylic acid amide SC_3012 cis-5-[1-(Cyclobutyl-methyl)-8-methylamino-2-oxo-8-phenyl- SC_3003 — SC_3045 461.3 1,3-diazaspiro[4.5]decan-3-yl]-4-methoxy-pyrimidine-2- carbonitrile SC_3013 cis-5-[8-Dimethylamino-1-[(1-hydroxy-cyclobutyl)-methyl]-2- INT-600 — SC_3013 461.3 oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-pyrimidine-2- carbonitrile SC_3014 cis-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8- INT-987 2-chloropyrimidine-5- SC_3014 445.3 phenyl-1,3-diazaspiro[4.5]decan-3-yl]-pyrimidine-5- carbonitrile carbonitrile SC_3015 cis-8-Dimethylamino-1-[(1-hydroxy-cyclobutyl)-methyl]-3-(2- INT-976 5-bromo-2- SC_3013 466.3 methoxy-pyrimidin-5-yl)-8-phenyl-1,3-diazaspiro[4.5]decan-2- methoxypyrimidine one (step 1); 1-(tert-butyldimethyl- silyloxy)cyclobutyl)methyl 4-methylbenzene-sulfonate (step 2) SC_3016 cis-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8- SC_3014 — SC_3016 463.3 phenyl-1,3-diazaspiro[4.5]decan-3-yl]-pyrimidine-5-carboxylic acid amide SC_3017 cis-4-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8- SC_3081 methanamine SC_3028 475.3 phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-methyl-benzamide SC_3018 cis-5-(8-Dimethylamino-2-oxo-8-phenyl-1-propyl-1,3- INT-600 1-bromopropane SC_3013 419.2 diazaspiro[4.5]decan-3-yl)-pyrimidine-2-carbonitrile SC_3019 cis-5-[8-Dimethylamino-1-(3-methoxy-propyl)-2-oxo-8- INT-600 1-bromo-3-methoxypropane SC-3013 449.3 phenyl-1,3-diazaspiro[4.5]decan-3-yl]-pyrimidine-2- carbonitrile SC_3020 cis-5-[1-(Cyclopropyl-methyl)-8-dimethylamino-2-oxo-8- INT-600 (bromomethyl)cyclopropane SC-3013 431.2 phenyl-1,3-diazaspiro[4.5]decan-3-yl]-pyrimidine-2- carbonitrile SC_3021 cis-4-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8- SC_3081 ammonia SC-3028 461.3 phenyl-1,3-diazaspiro[4.5]decan-3-yl]-benzamide SC_3022 cis-1-(Cyclobutyl-methyl)-8-dimethylamino-8-phenyl-3-[2- INT-987 5-bromo-2- SC_3022 488.3 (trifluoromethyl)-pyrimidin-5-yl]-1,3-diazaspiro[4.5]decan-2- (trifluoromethyl)pyrimidine one SC_3023 cis-8-Dimethylamino-1-[(1-hydroxy-cyclobutyl)-methyl]-3-(2- SC_3015 — SC_3023 452.3 hydroxy-pyrimidin-5-yl)-8-phenyl-1,3-diazaspiro[4.5]decan-2- one SC_3024 cis-5-[8-Dimethylamino-1-(2-methyl-propyl)-2-oxo-8-phenyl- INT-600 1-bromo-2-methylpropane SC_3013 433.3 1,3-diazaspiro[4.5]decan-3-yl]-pyrimidine-2-carbonitrile SC_3025 cis-5-[8-Dimethylamino-1-(2-hydroxy-ethyl)-2-oxo-8-phenyl- INT-600 (3-bromopropoxy)(tert- SC-3025 421.2 1,3-diazaspiro[4.5]decan-3-yl]-pyrimidine-2-carbonitrile butyl)dimethylsilane SC_3026 cis-5-[1-(Cyclobutyl-methyl)-8-methylamino-2-oxo-8-phenyl- SC_3078 — SC_3045 444.3 1,3-diazaspiro[4.5]decan-3-yl]-4-methyl-pyridine-2- carbonitrile SC_3027 cis-1-(Cyclobutyl-methyl)-3-(5-methoxy-pyrazin-2-yl)-8- SC_3075 — SC_3045 436.3 methylamino-8-phenyl-1,3-diazaspiro[4.5]decan-2-one SC_3028 cis-4-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8- SC_3081 — SC_3028 489.3 phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N,N-dimethyl- benzamide SC_3029 cis-4-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8- SC_3081 — SC_3028 533.3 phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-ethyl-N-(2-hydroxy- ethyl)-benzamide SC_3030 cis-2-[1-(Cyclobutyl-methyl)-8-methylamino-2-oxo-8-phenyl- SC_3008 — SC_3045 507.2 1,3-diazaspiro[4.5]decan-3-yl]-5-methylsulfonyl-benzonitrile SC_3031 cis-1-(Cyclobutyl-methyl)-8-methylamino-3-[2- SC_3084 — SC_3031 550.2 methylsulfonyl-4-(trifluoromethyl)-phenyl]-8-phenyl-1,3- diazaspiro[4.5]decan-2-one SC_3032 cis-4-[1-(Cyclobutyl-methyl)-8-methylamino-2-oxo-8-phenyl- SC_3089 — SC_3032 579.3 1,3-diazaspiro[4.5]decan-3-yl]-N,N-dimethyl-3- (trifluoromethyl)-benzenesulfonic acid amide SC_3033 cis-4-[1-(Cyclobutyl-methyl)-8-(ethyl-methyl-amino)-2-oxo-8- INT-797 4-bromobenzonitrile SC_3013 457.3 phenyl-1,3-diazaspiro[4.5]decan-3-yl]-benzonitrile (step 1); (bromomethyl)cyclobutane (step 2) SC_3034 cis-1-(Cyclobutyl-methyl)-8-(ethyl-methyl-amino)-8-phenyl-3- INT-797 5-bromo-2- SC-3013 502.3 [2-(trifluoromethyl)-pyrimidin-5-yl]-1,3-diazaspiro[4.5]decan- (trifluoromethyl)pyrimidine 2-one (step 1); (bromomethyl)cyclobutane (step 2) SC_3035 cis-5-[1-(Cyclobutyl-methyl)-8-(ethyl-methyl-amino)-2-oxo-8- INT-797 5-bromopyrimidine-2- SC_3013 459.3 phenyl-1,3-diazaspiro[4.5]decan-3-yl]-pyrimidine-2- carbonitrile (step 1); carbonitrile (bromomethyl)cyclobutane (step 2) SC_3036 cis-5-[8-Dimethylamino-1-[(1-methyl-cyclobutyl)-methyl]-2- INT-982 5-bromopyrimidine-2- SC_3022 459.3 oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-pyrimidine-2- carbonitrile carbonitrile SC_3037 cis-2-[3-(2-Cyano-pyrimidin-5-yl)-8-dimethylamino-2-oxo-8- INT-978 5-bromopyrimidine-2- SC_3065 462.3 phenyl-1,3-diazaspiro[4.5]decan-1-yl]-N,N-dimethyl- carbonitrile acetamide SC_3038 cis-1-(Cyclobutyl-methyl)-8-methylamino-8-phenyl-3-[2- SC_3022 — SC_3038 474.2 (trifluoromethyl)-pyrimidin-5-yl]-1,3-diazaspiro[4.5]decan-2- one SC_3039 cis-5-[8-Dimethylamino-8-(3-fluorophenyl)-1-(4-methoxy- INT-601 1-bromo-4-methoxybutane SC_3064 481.3 butyl)-2-oxo-1,3-diazaspiro[4.5]decan-3-yl]-pyrimidine-2- carbonitrile SC_3040 cis-5-[8-Dimethylamino-1-(3-methoxy-propyl)-2-oxo-8- INT-979 5-bromo-4- SC_3022 479.3 phenyl-1,3-diazaspiro[4.5]decan-3-yl]-4-methoxy-pyrimidine- methoxypyrimidine-2- 2-carbonitrile carbonitrile SC_3041 cis-5-[1-[(1-Cyano-cyclobutyl)-methyl]-8-dimethylamino-2- INT_600 (1-cyanocyclobutyl)methyl SC_3013 470.3 oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-pyrimidine-2- 4-methylbenzenesulfonate carbonitrile SC_3042 cis-N-(Cyclobutyl-methyl)-5-[1-(cyclobutyl-methyl)-8- INT-601 (bromomethyl)cyclobutane SC_3064 549.3 dimethylamino-8-(3-fluorophenyl)-2-oxo-1,3- diazaspiro[4.5]decan-3-yl]-pyrimidine-2-carboxylic acid amide SC_3043 cis-5-[1-(3-Methoxy-propyl)-8-methylamino-2-oxo-8-phenyl- SC_3019 — SC_3043 435.2 1,3-diazaspiro[4.5]decan-3-yl]-pyrimidine-2-carbonitrile SC_3044 cis-5-[8-Dimethylamino-8-(3-fluorophenyl)-1-methyl-2-oxo- INT_600 iodomethane SC_3013 409.2 1,3-diazaspiro[4.5]decan-3-yl]-pyrimidine-2-carbonitrile SC_3045 cis-4-Methoxy-5-[1-(3-methoxy-propyl)-8-methylamino-2- SC_3040 — SC_3045 465.3 oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-pyrimidine-2- carbonitrile SC_3046 cis-4-[8-Dimethylamino-1-(2-methoxy-ethyl)-2-oxo-8-phenyl- INT-980 4-bromopyrimidine-2- SC_3022 435.2 1,3-diazaspiro[4.5]decan-3-yl]-pyrimidine-2-carbonitrile carbonitrile SC_3047 cis-5-[8-Dimethylamino-1-(2-methoxy-ethyl)-2-oxo-8-phenyl- INT-980 5-bromo-4- SC_3022 465.3 1,3-diazaspiro[4.5]decan-3-yl]-4-methoxy-pyrimidine-2- methoxypyrimidine-2- carbonitrile carbonitrile SC_3048 cis-4-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8- INT-987 4-bromopyrimidine-2- SC_3022 445.3 phenyl-1,3-diazaspiro[4.5]decan-3-yl]-pyrimidine-2- carbonitrile carbonitrile SC_3049 cis-1-(Cyclobutyl-methyl)-8-dimethylamino-3-(6- INT-987 4-bromo-6-(methylthio)- SC_3022 466.3 methylsulfanyl-pyrimidin-4-yl)-8-phenyl-1,3- pyrimidine diazaspiro[4.5]decan-2-one SC_3050 cis-2-[3-(2-Cyano-pyrimidin-4-yl)-8-dimethylamino-2-oxo-8- SC_3022 4-bromopyrimidine-2- SC_3022 462.3 phenyl-1,3-diazaspiro[4.5]decan-1-yl]-N,N-dimethyl- carbonitrile acetamide SC_3051 cis-6-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8- INT-987 6-bromopyrimidine-4- SC_3022 445.3 phenyl-1,3-diazaspiro[4.5]decan-3-yl]-pyrimidine-4- carbonitrile carbonitrile SC_3052 cis-2-(8-Dimethylamino-2-oxo-3,8-diphenyl-1,3- INT-987 bromobenzene SC_3022 435.3 diazaspiro[4.5]decan-1-yl)-N,N-dimethyl-acetamide SC_3053 cis-1-(Cyclobutyl-methyl)-8-dimethylamino-3,8-diphenyl-1,3- INT-987 bromobenzene SC_3022 418.3 diazaspiro[4.5]decan-2-one SC_3054 cis-2-[8-Dimethylamino-1-(2-methoxy-ethyl)-2-oxo-8-phenyl- INT-980 5-chloropyrimidine-2- SC_3022 435.2 1,3-diazaspiro[4.5]decan-3-yl]-pyrimidine-5-carbonitrile carbonitrile SC_3055 cis-8-Dimethylamino-1-(2-methoxy-ethyl)-3,8-diphenyl-1,3- INT-980 bromobenzene SC_3022 408.3 diazaspiro[4.5]decan-2-one SC_3056 cis-5-[8-Dimethylamino-1-(2-methoxy-ethyl)-2-oxo-8-phenyl- INT-980 5-bromo-4- SC_3022 448.3 1,3-diazaspiro[4.5]decan-3-yl]-4-methyl-pyridine-2- methylpicolinonitrile carbonitrile SC_3057 cis-N,N-Dimethyl-2-(8-methylamino-2-oxo-3,8-diphenyl-1,3- SC_3052 — SC_3045 421.3 diazaspiro[4.5]decan-1-yl)-acetamide SC_3058 cis-5-[1-[(1-Cyano-cyclobutyl)-methyl]-8-methylamino-2-oxo- SC_3041 — SC_3058 456.2 8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-pyrimidine-2- carbonitrile SC_3059 cis-5-[1-[(1-Cyano-cyclobutyl)-methyl]-8-(ethyl-methyl- INT-797 5-bromopyrimidine-2- SC_3013 484.3 amino)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]- carbonitrile (step 1); pyrimidine-2-carbonitrile 1-(bromo- methyl)cyclobutane- carbonitrile (step 2) SC_3060 CIS-4-[8-Dimethylamino-1-[(1-hydroxy-cyclobutyl)-methyl]- INT-987 4-bromobenzonitrile SC_3013 459.3 2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-benzonitrile (step 1); (1-(tert- butyldimethylsilyloxy)cyclo- butyl)methyl 4- methylbenzene-sulfonate (2 step) SC_3061 cis-3-[8-Dimethylamino-1-[(1-hydroxy-cyclobutyl)-methyl]-2- INT-987 3-bromobenzonitrile SC_3013 459.3 oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-benzonitrile (step 1); (1-(tert- butyldimethylsilyloxy)cyclo- butyl)methyl 4- methylbenzene-sulfonate (step 2) SC_3063 cis-5-[1-[(1-Cyano-cyclobutyl)-methyl]-8-dimethylamino-2- INT-987 5-bromopicolinonitrile (step SC_3013 469.3 oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-pyridine-2- 1); 1-(bromomethyl)cyclo- carbonitrile butanecarbonitrile (step 2) SC_3064 cis-2-[3-(2-Cyano-pyrimidin-5-yl)-8-dimethylamino-2-oxo-8- INT-600 2-bromo-N-propylacetamide SC_3064 476.3 phenyl-1,3-diazaspiro[4.5]decan-1-yl]-N-propyl-acetamide SC_3065 cis-5-[1-(Cyclobutyl-methyl)-8-(ethyl-methyl-amino)-2-oxo-8- INT-986 5-bromo-4- SC_3065 489.3 phenyl-1,3-diazaspiro[4.5]decan-3-yl]-4-methoxy-pyrimidine- methoxypyrimidine-2- 2-carbonitrile carbonitrile SC_3066 cis-4-[1-(Cyclobutyl-methyl)-8-methylamino-2-oxo-8-phenyl- SC_3080 — SC_3066 459.3 1,3-diazaspiro[4.5]decan-3-yl]-3-methoxy-benzonitrile SC_3067 cis-5-[8-Dimethylamino-1-(3-methoxy-propyl)-2-oxo-8- INT-979 5-bromo-6- SC_3022 478.3 phenyl-1,3-diazaspiro[4.5]decan-3-yl]-6-methoxy-pyridine-2- methoxypicolinonitrile carbonitrile SC_3068 cis-4-[8-Dimethylamino-1-[(1-hydroxy-cyclobutyl)-methyl]-2- SC_3060 — SC_3016 477.3 oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-benzamide SC_3069 cis-5-[8-Dimethylamino-1-[(1-hydroxy-cyclobutyl)-methyl]-2- INT-976 5-bromopicolinonitrile (step SC_3013 460.3 oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-pyridine-2- 1); 1-(tert-butyldimethyl- carbonitrile silyloxy)cyclobutyl)methyl 4-methylbenzene-sulfonate (step 2) SC_3070 cis-5-[8-Dimethylamino-1-[(1-hydroxy-cyclobutyl)-methyl]-2- INT-976 5-bromopicolinonitrile (step SC_3013 562.3 oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-[(1-hydroxy- 1); 1-(tert-butyldimethyl- cyclobutyl)-methyl]-pyridine-2-carboxylic acid amide silyloxy)cyclobutyl)methyl 4-methylbenzene-sulfonate (step 2) SC_3071 cis-2-[8-Dimethylamino-1-[(1-hydroxy-cyclobutyl)-methyl]-2- INT-976 2-bromobenzonitrile (step SC_3013 459.3 oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-benzonitrile 1); 1-(tert-butyldimethyl- silyloxy)cyclobutyl)methyl 4-methylbenzene-sulfonate (step 2) SC_3072 cis-3-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8- INT-987 3-iodobenzonitrile SC_3022 443.3 phenyl-1,3-diazaspiro[4.5]decan-3-yl]-benzonitrile SC_3073 cis-1-(Cyclobutyl-methyl)-8-dimethylamino-8-phenyl-3-[2- INT-987 5-bromo-2- SC_3022 488.3 (trifluoromethyl)-pyrimidin-5-yl]-1,3-diazaspiro[4.5]decan-2- (trifluoromethyl)pyrimidine one SC_3074 cis-5-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8- INT-987 methyl 5-bromo-4-methyl- SC_3022 491.3 phenyl-1,3-diazaspiro[4.5]decan-3-yl]-4-methyl-pyridine-2- picolinate carboxylic acid methyl ester SC_3075 cis-1-(Cyclobutyl-methyl)-8-dimethylamino-3-(5-methoxy- INT-987 2-bromo-5-methoxypyrazine SC_3022 450.3 pyrazin-2-yl)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one SC_3076 cis-1-(Cyclobutyl-methyl)-8-dimethylamino-3-(2-methoxy- INT-987 5-bromo-2- SC_3022 450.3 pyrimidin-5-yl)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one methoxypyrimidine SC_3077 cis-4-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8- INT-987 4-iodobenzonitrile SC_3022 443.3 phenyl-1,3-diazaspiro[4.5]decan-3-yl]-benzonitrile SC_3078 cis-5-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8- INT-987 5-bromo-4- SC_3022 458.3 phenyl-1,3-diazaspiro[4.5]decan-3-yl]-4-methyl-pyridine-2- methylpicolinonitrile carbonitrile SC_3079 cis-1-(Cyclobutyl-methyl)-8-dimethylamino-3-(5-fluoro- INT-987 2-bromo-5-fluoropyrimidine SC_3022 438.3 pyrimidin-2-yl)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one SC_3080 cis-4-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8- INT-987 4-bromo-3- SC_3022 473.3 phenyl-1,3-diazaspiro[4.5]decan-3-yl]-3-methoxy-benzonitrile methoxybenzonitrile SC_3081 cis-4-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8- INT-987 methyl 4-iodobenzoate SC_3022 476.3 phenyl-1,3-diazaspiro[4.5]decan-3-yl]-benzoic acid methyl ester SC_3082 cis-1-(Cyclobutyl-methyl)-8-dimethylamino-8-phenyl-3-(2- INT-987 4-iodo-2-(pyrrolidin-1- SC_3022 489.3 pyrrolidin-1-yl-pyrimidin-4-yl)-1,3-diazaspiro[4.5]decan-2-one yl)pyrimidine SC_3083 cis-1-(Cyclobutyl-methyl)-8-dimethylamino-8-phenyl-3-(5- INT-987 2-(5-bromothiophen-2- SC_3022 501.3 pyridin-2-yl-thiophen-2-yl)-1,3-diazaspiro[4.5]decan-2-one yl)pyridine SC_3084 cis-1-(Cyclobutyl-methyl)-8-dimethylamino-3[2- INT-987 1-bromo-2- SC_3022 564.2 methylsulfonyl-4-(trifluoromethyl)-phenyl]-8-phenyl-1,3- (methylsulfonyl)-4- diazaspiro[4.5]decan-2-one (trifluoromethyl)benzene SC_3085 cis-1-(Cyclobutyl-methyl)-8-dimethylamino-8-phenyl-3-[6- INT-987 5-bromo-2- SC_3022 487.3 (trifluoromethyl)-pyridin-3-yl]-1,3-diazaspiro[4.5]decan-2-one (trifluoromethyl)pyridine SC_3086 cis-1-(Cyclobutyl-methyl)-3-(2,4-dimethoxy-phenyl)-8- INT-987 1-bromo-2,4- SC_3022 478.3 dimethylamino-8-phenyl-1,3-diazaspiro[4.5]decan-2-one dimethoxybenzene SC_3087 cis-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8- INT 987 2-iodo-4-(methylthio)- SC_3022/ 521.3 phenyl-1,3-diazaspiro[4.5]decan-3-yl]-4-methylsulfonyl- benzonitrile (SC_3022) SC_3008 benzonitrile SC_3088 cis-5-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8- INT-987 5-bromo-2- SC_3022 461.3 phenyl-1,3-diazaspiro[4.5]decan-3-yl]-2-fluoro-benzonitrile fluorobenzonitrile SC_3089 cis-4-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8- INT-987 4-bromo-N,N-dimethyl-3- SC_3022 593.3 phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N,N-dimethyl-3- (trifluoromethyl)benzene- (trifluoromethyl)-benzenesulfonic acid amide sulfonamide SC_3090 cis-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8- INT-987 2-bromobenzonitrile SC_3022 443.3 phenyl-1,3-diazaspiro[4.5]decan-3-yl]-benzonitrile SC_3091 cis-1-(Cyclobutyl-methyl)-8-dimethylamino-3-(2-methyl- INT-987 6-bromo-2- SC_3022 473.3 imidazo[1,2-a]pyrazin-6-yl)-8-phenyl-1,3- methylimidazo[1,2- diazaspiro[4.5]decan-2-one a]pyrazine SC_3092 cis-1-(Cyclobutyl-methyl)-8-dimethylamino-3-(4- INT-987 (4- SC_3022/ 496.3 methylsulfonyl-phenyl)-8-phenyl-1,3-diazaspiro[4.5]decan-2- iodophenyl)(methyl)sulfane SC_3008 one SC_3093 cis-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8- INT-987 2-bromo-5- SC_3022 473.3 phenyl-1,3-diazaspiro[4.5]decan-3-yl]-5-methoxy-benzonitrile methoxybenzonitrile SC_3094 cis-1-(Cyclobutyl-methyl)-8-dimethylamino-3,8-diphenyl-1,3- INT-987 bromobenzene SC_3022 418.3 diazaspiro[4.5]decan-2-one SC_3096 cis-1-(Cyclobutyl-methyl)-8-dimethylamino-8-phenyl-3- INT-987 2-bromopyrazine SC_3022 420.3 pyrazin-2-yl-1,3-diazaspiro[4.5]decan-2-one

Example Chemical name Reactant I Reactant II in analogy to method ¹H NMR data m/z (M + H)⁺ SC_3098 cis-8-Dimethylamino-1-[(1- INT-799 5-bromo-2-(4-methylpiperazin-1- SC_3097 1H NMR (DMSO-d6): δ 8.56 (s, 2H), 7.36- 534.4 hydroxy-cyclobutyl)-methyl]-3- yl)pyrimidine 7.35 (m, 4H), 7.27-7.24 (m, 1H), 5.52 (s, [2-(4-methyl-piperazin-1-yl)- 1H), 3.71 (s, 2H), 3.64 (m, 4H), 3.21 (s, 2H), pyrimidin-5-yl]-8-phenyl-1,3- 2.69-2.67 (m, 2H), 2.32 (m, 4H), 2.19-2.11 diazaspiro[4.5]decan-2-one (m, 7H), 1.98 (s, 6H), 1.92-1.86 (m, 2H), 1.66-1.64 (m, 1H), 1.52-1.42 (m, 5H). SC_3101 cis-1-[(1-Hydroxy-cyclobutyl)- SC_3098 SC_3099 1H NMR (DMSO-d6): δ 8.58 (s, 2H), 7.48 520.4 methyl]-8-methylamino-3-[2-(4- (d, 2H), 7.32 (t, 2H), 7.19 (t, 1H), 5.61 (s, methyl-piperazin-1-yl)-pyrimidin- 1H), 3.75 (s, 2H), 3.66-3.64 (m, 4H), 3.30 (s, 5-yl]-8-phenyl-1,3- 2H), 2.35-2.32 (m, 4H), 2.25-2.19 (m, 5H), diazaspiro[4.5]decan-2-one 2.12-2.07 (m, 2H), 1.90-1.88 (m, 7H), 1.79- 1.73 (m, 2H), 1.65-1.63 (m, 1H), 1.50-1.44 (m, 3H) SC_3102 cis-1-[(1-Hydroxy-cyclobutyl)- SC_3100 SC_3099 1H NMR (DMSO-d6): δ 9.51 (br s, 2H), 506.3 methyl]-8-methylamino-8-phenyl- 9.15 (br s, 2H), 8.65 (s, 2H), 7.69-7.68 (m, 3-(2-piperazin-1-yl-pyrimidin-5- 2H), 7.50-7.41 (m, 3H), 3.88-3.86 (m, 4H), yl)-1,3-diazaspiro[4.5]decan-2-one 3.79 (m, 2H), 3.65 (m, 2H), 3.16-3.13 (m, dihydrochloride 4H), 2.64-2.62 (m, 2H), 2.38-2.33 (m, 2H), 2.16-2.04 (m, 7H), 1.90-1.84 (m, 2H), 1.76- 1.70 (m, 3H), 1.60-1.58 (m, 1H). SC_3104 cis-1-(Cyclobutyl-methyl)-8- SC_3103 SC_3099 1H NMR (DMSO-d6): δ 8.59 (s, 1H), 7.81 487.3 methylamino-3-[4-methyl-6- (s, 1H), 7.44 (d, 2H), 7.30 (t, 2H), 7.17 (t, (trifluoromethyl)-pyridin-3-yl]-8- 1H), 3.76 (s, 2H), 3.21 (d, 2H), 2.61-2.57 (m, phenyl-1,3-diazaspiro[4.5]decan-2- 1H), 2.32 (s, 3H), 2.29-2.17 (m, 3H), 2.03- one 1.97 (m, 2H), 1.91-1.88 (m, 5H), 1.84-1.67 (m, 6H), 1.51-1.48 (m, 2H). SC_3106 cis-1-(Cyclopropyl-methyl)-8- SC_3105 SC_3099 1H NMR (DMSO-d6): δ 7.90-7.88 (d, 2H), 468.2 methylamino-3-(4-methylsulfonyl- 7.82-7.80 (d, 2H), 7.50-7.48 (d, 2H), 7.35- phenyl)-8-phenyl-1,3- 7.32 (m, 2H), 7.22-7.19 (m, 1H), 3.80 (s, diazaspiro[4.5]decan-2-one 2H), 3.14-3.10 (m, 5H), 2.29-2.23 (m, 3H), 1.91-1.79 (m, 7H), 1.42-1.39 (m, 2H), 1.05- 1.04 (m, 1H), 0.50-0.47 (m, 2H), 0.34-0.32 (m, 2H). SC_3107 cis-1-(Cyclopropyl-methyl)-8- INT-983 1-bromo-2-fluoro-4- SC3103 (step 1), 1H NMR (DMSO-d6): δ 7.85 (t, 1H), 7.79- 500.2 dimethylamino-3-(2-fluoro-4- (methylsulfonyl)benzene (step 1), SC_3105 (step 2) 7.76 (m, 1H), 7.72-7.69 (m, 1H), 7.37-7.33 methylsulfonyl-phenyl)-8-phenyl- (Bromomethyl)cyclopropane (step 2) (m, 4H), 7.27-7.24 (m, 1H), 3.81 (s, 2H), 1,3-diazaspiro[4.5]decan-2-one 3.24 (s, 3H), 3.07 (d, 2H), 2.71-2.68 (m, 2H), 2.28-2.22 (m, 2H), 1.99 (s, 6H), 1.53-1.42 (m, 4H), 1.00-0.99 (m, 1H), 0.53-0.49 (m, 2H), 0.34-0.30 (m, 2H). SC_3108 cis-2-[8-Dimethylamino-1-[(1- SC_3071 SC_3016 1H NMR (600 MHz, DMSO) δ 7.59-7.55 477.3 hydroxy-cyclobutyl)-methyl]-2- (s, 1H), 7.47-7.39 (m, 2H), 7.39-7.31 (m, oxo-8-phenyl-1,3- 5H), 7.30-7.21 (m, 3H), 3.77-3.73 (s, diazaspiro[4.5]decan-3-yl]- 2H), 3.21-3.17 (s, 1H), 2.72-2.66 (d, 2H), benzamide; formic acid 2.17-2.09 (m, 5H), 2.02-1.99 (s, 6H), 1.95-1.86 (m, 2H), 1.71-1.60 (m, 3H), 1.49-1.37 (m, 3H) SC_3109 cis-2-[8-Dimethylamino-1-[2-(1- INT988 2-bromobenzonitrile SC_3097 (step 1), 1H NMR (600 MHz, DMSO) δ 7.52-7.48 505.3 methoxy-cyclobutyl)-ethyl]-2-oxo- SC_3109 (step 2) (s, 1H), 7.47-7.31 (m, 7H), 7.29-7.23 (m, 8-phenyl-1,3-diazaspiro[4.5]decan- 1H), 7.25-7.22 (s, 1H), 7.24-7.18 (m, 3-yl]-benzamide 1H), 3.68-3.65 (s, 3H), 3.13-3.10 (s, 2H), 3.09-3.02 (m, 2H), 2.71-2.65 (m, 2H), 2.21-2.12 (m, 2H), 2.09-1.99 (m, 2H), 2.02-1.98 (s, 6H), 1.97-1.86 (m, 4H), 1.77-1.67 (m, 1H), 1.64-1.52 (m, 3H), 1.44-1.36 (td, 2H). SC_3110 cis-8-Dimethylamino-1-[2-(1- INT-988 5-bromo2-methyl-pyrimidine SC_3103 1H NMR (600 MHz, DMSO) δ 8.94-8.90 478.3 methoxy-cyclobutyl)-ethyl]-3-(2- (s, 2H), 7.41-7.34 (d, 4H), 7.32-7.24 methyl-pyrimidin-5-yl)-8-phenyl- (ddd, 1H), 3.76-3.72 (s, 2H), 3.15-3.08 1,3-diazaspiro[4.5]decan-2-one (m, 5H), 2.72-2.65 (m, 2H), 2.57-2.52 (s, 3H), 2.25-2.16 (m, 2H), 2.11-2.02 (m, 2H), 2.03-1.99 (s, 6H), 1.99-1.86 (m, 4H), 1.78-1.68 (tq, 1H), 1.65-1.51 (m, 3H), 1.50-1.44 (d, 2H). SC_3111 cis-5-[1-[(1-Hydroxy-cyclobutyl)- INT-799 5-bromo-2-cyanopyrimidine SC_3103 (step 1), 1H NMR (600 MHz, DMSO) δ 9.24-9.20 447.3 methyl]-8-methylamino-2-oxo-8- SC_3099 (step 2) (s, 2H), 7.53-7.48 (m, 2H), 7.37-7.31 (t, phenyl-1,3-diazaspiro[4.5]decan-3- 2H), 7.25-7.19 (t, 1H), 3.93-3.89 (s, 2H), yl]-pyrimidine-2-carbonitrile 3.42-3.36 (m, 2H), 2.35-2.26 (td, 2H), 2.18-2.10 (tt, 2H), 2.09-2.04 (s, 1H), 1.97- 1.88 (m, 2H), 1.93-1.90 (s, 6H), 1.86- 1.77 (td, 2H), 1.72-1.62 (s, 1H), 1.59- 1.54 (d, 1H), 1.48-1.43 (d, 2H). SC_3113 cis-4-[1-[(1-Hydroxy-cyclobutyl)- INT-976 1-bromo-4-cyano-2- SC_3112 1HNMR (DMSO-d6, 400 MHz), δ (ppm) = 475.3 methyl]-8-methylamino-2-oxo-8- methoxybenzene (step 1) 7.54 (s, 1H), 7.50 (d, 1H, J = 8.16 Hz), 7.46- phenyl-1,3-diazaspiro[4.5]decan-3- 7.39 (m, 3H), 7.30 (t, 2H, J = 7.48 Hz), 7.18 yl]-3-methoxy-benzonitrile (t, 1H, J = 7.16 Hz), 5.59 (s, 1H), 3.85 (s, 3H), 3.73 (s, 2H), 3.30 (s, 2H, merged with DMSO-water), 2.32-2.08 (m, 4H), 1.91-1.87 (m, 7H), 1.68-1.47 (m, 6H). SC_3114 cis-4-[8-Ethylamino-1-[(1- INT-1008 4-Bromo-3-methoxy- SC_3112 (step 1, step 2) 1HNMR (DMSO-d6, 400 MHz), δ (ppm) = 489.1 hydroxy-cyclobutyl)-methyl]- benzonitrile (step 1) 7.54 (s, 1H), 7.51-7.45 (m, 3H), 7.40 (d, 1H, 2-oxo-8-phenyl-1,3- J = 8.24 Hz), 7.29 (t, 2H, J = 7.58 Hz), 7.17 diazaspiro[4.5]decan-3- (t, 1H, J = 7.12 (Hz), 5.60 (s, 1H), 3.85 (s, yl]-3-methoxy-benzonitrile 3H), 3.73 (s, 2H), 3.21 (s, 2H, merged with DMSO—H2O), 2.32-2.27 (m, 2H), 2.08 (bs, 5H), 1.96-1.87 (m, 4H), 1.68-1.46 (m, 6H), 0.97 (t, 3H, J = 4.0 Hz). SC_3115 cis-2-[8-Ethylamino-1-[(1- INT-1008 2-bromo-benzonitrile (step 1) SC_3112 (step 1, step 2) 1HNMR (DMSO-d6, 400 MHz), δ (ppm) = 458.9 hydroxy-cyclobutyl)-methyl]- 7.82 (d, 1H, J = 7.56 Hz), 7.71 (t, 1H, J = 2-oxo-8-phenyl-1,3- 6.98 Hz), 7.53-7.47 (m, 3H), 7.37-7.27 (m, diazaspiro[4.5]decan-3- 3H), 7.19-7.17 (m, 1H), 5.55 (s, 1H), 3.87 (s, yl]-benzonitrile 2H), 3.38 (s, 2H), 2.36-2.32 (m, 2H), 2.10 (bs, 4H), 1.94-1.86 (m. 4H), 1.75-1.48 (6H), 0.98 (bs, 3H). SC_3116 cis-5-[1-[(1-Hydroxy-cyclobutyl)- INT-799 5-bromo-4-methoxy-pyrimidine-2- SC_3103 (step 1), 1HNMR (DMSO-d6, 400 MHz, at 100 0 C.), 477.2 methyl]-8-methylamino-2-oxo-8- carbonitrile (step 1) SC_3099 (step 2) δ (ppm) = 8.79 (s, 1H), 7.46 (d, 2H, J = 7.84 phenyl-1,3-diazaspiro[4.5]decan-3- Hz), 7.32 (t, 2H, J = 7.12 Hz), 7.19 (t, 1H, J = yl]-4-methoxy-pyrimidine-2- 7.28 Hz), 5.09 (bs, 1H), 4.05 (s, 3H), 3.85 carbonitrile (s, 2H), 3.38 (s, 2H), 2.31-2.15 (m, 4H), 1.98 (m, 7H), 1.74-1.51 (m, 6H). SC_3117 cis-2-[8-Dimethylamino-1-(oxetan- SC_3274 toluene-4-sulfonic acid oxetan-3- SC_3105 (step 1), 1HNMR (DMSO-d6, 400 MHz), δ (ppm) = 463.4 3-yl-methyl)-2-oxo-8-phenyl-1,3- ylmethyl ester (step 1) SC_3016 (step 2) 7.52 (s,1H), 7.43-7.33 (m, 6H), 7.30-7.17 diazaspiro[4.5]decan-3-yl]- (m, 4H), 4.63 (t, 2H, J = 6.9 Hz), 4.39 (t, 2H, benzamide J = 6.08 Hz), 3.64 (s, 2H), 3.38 (d, 2H, J = 7.32 Hz), 3.21-3.15 (m, 1H), 2.70-2.66 (m, 2H), 2.08-1.98 (m, 8H), 1.54-1.35 (m, 4H). SC_3118 cis-4-Methoxy-5-(8-methylamino- INT-976 5-bromo-4-methoxy-pyrimidine-2- SC_3103 (step 1), 1HNMR (DMS0-d6, 400 MHz), δ (ppm) = 393.0 2-oxo-8-phenyl-1,3- carbonitrile (step 1) SC_3099 (step 2) 8.80 (s, 1H), 7.86 (bs, 1H), 7.43 (d, 2H, J = diazaspiro[4.5]decan-3-yl)- 7.84 Hz), 7.32 (t, 2H, J = 7.32 Hz), 7.21-7.18 pyrimidine-2-carbonitrile (m, 1H), 4.02 (s, 3H), 3.83 (s, 2H), 2.07-2.00 (m, 3H), 1.90-1.74 (m, 7H), 1.48 (d, 2H, J = 13.8 Hz). SC_3119 cis-2-(8-Methylamino-2-oxo-8- INT-976 2-bromo-benzonitrile (step 1) SC_3103 (step 1), 1HNMR (DMSO-d6, 400 MHz) δ 7.51 (bs, 379.4 phenyl-1,3-diazaspiro[4.5]decan-3- SC_3099 (step 2), 1H), 7.43-7.37 (m, 4H), 7.33-2.29 (m, 3H, yl)-benzamide SC_3016 (step 3) J = 8.28 Hz), 7.22-7.16 (m, 3H), 6.93 (bs, 1H), 3.64 (s, 2H), 2.03-1.97 (m, 2H), 1.86 (bs, 5H), 1.73-1.58 (m, 4H). SC_3121 cis-3-(2-Cyclopropyl-pyrimidin-5- INT-976 5-bromo-2-cyclopropyl- SC_3103 1H NMR (600 MHz, DMSO) δ 8.80 (s, 2H), 392.3 yl)-8-dimethylamino-8-phenyl-1,3- pyrimidine 7.67 (s, 1H), 7.41-7.32 (m, 4H), 7.31- diazaspiro[4.5]decan-2-one 7.22 (ddt, 1H), 3.60 (s, 2H), 2.42-2.36 (m, 2H), 2.18-2.08 (m, 1H), 1.98-1.85 (m, 4H), 1.96 (s, 6H), 1.47 (s, 2H), 0.98-0.91 (m, 2H), 0.93-0.86 (m, 2H). SC_3122 cis-8-Dimethylamino-3-[4-methyl- INT-976 5-bromo-4-methyl-2- SC_3103 1H NMR (600 MHz, DMSO) δ 8.57 (s, 1H), 433.2 6-(trifluoromethyl)-pyridin-3-yl]-8- (trifluoromethyl)pyridine 7.79 (s, 1H), 7.52 (s, 1H), 7.40-7.32 (m, phenyl-1,3-diazaspiro[4.5]decan-2- 4H), 7.30-7.22 (tt, 1H), 3.61 (s, 2H), 2.39- one 2.30 (m, 5H), 1.96 (s, 6H), 2.00-1.91 (m, 2H), 1.84 (s, 2H), 1.57-1.53 (s, 2H). SC_3123 cis-8-Dimethylamino-3-(2- INT-976 1-bromo-2-methylsulfonyl- SC_3103 1H NMR (600 MHz, DMSO) δ 7.98-7.92 428.2 methylsulfonyl-phenyl)-8-phenyl- benzene (dd, 1H), 7.81-7.74 (td, 1H), 7.61-7.54 1,3-diazaspiro[4.5]decan-2-one (td, 1H), 7.52-7.46 (m, 2H), 7.41-7.31 (m, 2H), 7.35 (s, 2H), 7.29-7.22 (tt, 1H), 3.49 (s, 2H), 3.25 (s, 3H), 2.37 (s, 2H), 1.99- 1.96 (m, 1H), 1.98-1.94 (s, 6H), 1.95- 1.91 (d, 1H), 1.83-1.79 (m, 2H), 1.58- 1.55 (s, 2H). SC_3124 cis-8-Dimethylamino-8-phenyl-3- INT-989 Piperazine-2-one SC_3120 1H NMR (600 MHz, DMSO) δ 8.52 (s, 2H), 436.3 (2-piperazin-1-yl-pyrimidin-5-yl)- 7.41-7.31 (m, 5H), 3.59-3.54 (m, 4H), 1,3-diazaspiro[4.5]decan-2-one 3.52 (s, 2H), 2.76-2.70 (m, 4H), 2.55 (s, 3H), 2.49-2.33 (m, 2H), 1.96 (s, 6H), 1.93- 1.83 (m, 4H), 1.51-1.43 (s, 2H). SC_3125 trans-2-(8-Ethylamino-2-oxo-8- SC_3127 SC_3016 1HNMR (DMSO-d6, 400 MHz), δ (ppm) = 393.1 phenyl-1,3-diazaspiro[4.5]decan-3- 7.56-7.20 (m, 12H), 3.60 (s, 2H), 2.08-1.92 yl)-benzamide (m, 6H), 1.69 (bs, 2H), 1.56 (bs, 2H), 0.93 (t, 3H). SC_3126 cis--2-(8-Ethylamino-2-oxo-8- SC_3128 SC_3016 ¹HNMR (DMSO-d₆, 400 MHz), δ (ppm) = 393.4 phenyl-1,3-diazaspiro[4.5]decan-3- 7.51-2.38 (m, 5H), 7.32-7.30 (m, 3H), 7.22- yl)-benzamide 7.18 (m, 3H), 6.93 (s, 1H), 3.63 (s, 2H), 2.07-1.98 (m, 4H), 1.86-1.72 (m, 4H), 1.60- 1.57 (m, 2H), 0.93 (t, 3H). SC_3127 cis-2-(8-Ethylamino-2-oxo-8- INT-1009 2-bromo-benzonitrile SC_3103 1HNMR (DMSO-d6, 400 MHz), δ (ppm) = 375.1 phenyl-1,3-diazaspiro[4.5]decan-3- 7.77 (d, 1H, J = 6.8 Hz), 7.69-7.65 (m, 1H), yl)-benzonitrile 7.51 (d, 1H, J = 8.4 Hz), 7.44 (d, 2H, J = 7.6 Hz), 7.39 (s, 1H), 7.34-7.28 (m, 3H), 7.17 (t, 1H, 7.2 Hz), 3.77 (s, 2H), 2.10-2.04 (m, 4H), 1.91-1.88 (m, 2H), 1.80-1.74 (m, 3H), 1.61- 1.58 (m, 2H), 0.94 (t, 3H, J = 6.8 Hz). SC_3128 cis-2-(8-Ethylamino-2-oxo-8- INT-1008 2-bromo-benzonitrile SC_3103 ¹HNMR (DMSO-d₆, 400 MHz), δ (ppm) = 375.1 phenyl-1,3-diazaspiro[4.5]decan-3- 7.89 (bs, 1H), 7.79 (d, 1H, J = 7.6), 7.69 (t, yl)-benzonitrile 1H, J = 7.6 Hz), 7.54-7.50 (m, 3H), 7.36- 7.30 (m, 3H), 7.18 (t, 1H, J = 7.2 Hz), 3.73 (s, 2H), 2.08-1.92 (m, 7H), 1.71 (bs, 2H), 1.59 (bs, 2H,), 0.93 (t, 3H, J = 6.4 Hz). SC_3131 cis-3-[5-(8-Dimethylamino-2-oxo- SC_3129 SC_3016 1H NMR (600 MHz, DMSO) δ 9.11 (s, 2H), 471.3 8-phenyl-1,3-diazaspiro[4.5]decan- 8.79 (t, 1H), 8.43 (dt, 1H), 8.09 (s, 1H), 7.94 3-yl)-pyrimidin-2-yl]-benzamide (dt, 1H), 7.84 (s, 1H), 7.56 (t, 1H), 7.41- 7.35 (m, 4H), 7.28 (ddd, 1H), 3.72 (s, 2H), 2.00-1.84 (m, 2H), 1.98 (s, 6H), 1.53 (s, 2H). SC_3134 trans-4-(8-Ethylamino-2-oxo-8- INT-1009 4-Bromo-3-methoxy-benzonitrile SC_3103 1HNMR (DMSO-d6, 400 MHz), δ (ppm) = 405.3 phenyl-1,3-diazaspiro[4.5]decan-3- 7.71 (bs, 1H), 7.56-7.49 (m, 4H), 7.37 (d, yl)-3-methoxy-benzonitrile 1H, J = 6.6 Hz), 7.31 (t, 2H, J = 7.10 Hz), 7.19-7.17 (m, 1H), 3.87 (s, 3H), 3.62 (s, 2H), 2.06-1.90 (m, 7H), 1.69-1.53 (m, 4H), 0.92 (t, 3H, J = 6.70 Hz). SC_3135 cis-4-(8-Ethylamino-2-oxo-8- INT-1008 4-Bromo-3-methoxy-benzonitrile SC_3103 1HNMR (DMSO-d6, 400 MHz), δ (ppm) = 405.2 phenyl-1,3-diazaspiro[4.5]decan-3- 7.52-7.50 (m, 2H), 7.44-7.43 (m, 2H), 736 yl)-3-methoxy-benzonitrile (d, 1H, J = 8.04 Hz), 7.30-7.19 (m, 4H), 3.83 (s, 3H), 3.63 (s, 2H), 2.05-1.72 (m, 8H), 1.53-1.50 (m, 2H), 0.92 (t, 3H). SC_3136 cis-3-[2-(4-Acetyl-piperazin-1-yl)- SC_3124 acetyl chloride SC_3130 478.3 pyrimidin-5-yl]-8-dimethylamino- 8-phenyl-1,3-diazaspiro[4.5]decan- 2-one SC_3137 cis-8-Dimethylamino-8-phenyl-3- INT-989 pyridine-4-boronic acid SC_3129 1H NMR (600 MHz, DMSO) δ 9.16 (s, 2H), 429.2 (2-pyridin-4-yl-pyrimidin-5-yl)-1,3- 8.70 (d, 1H), 8.18 (s, 1H), 7.91 (s, 1H), 7.42- diazaspiro[4.5]decan-2-one 7.35 (m, 4H), 7.28 (tt, 1H), 3.73 (s, 2H), 2.49-2.37 (m, 2H), 1.98 (s, 6H), 2.01-1.87 (m, 2H), 1.58-1.47 (m, 2H). SC_3138 cis-8-Dimethylamino-8-phenyl-3- INT-989 pyridine-3-boronic acid SC_3129 1H NMR (600 MHz, DMSO) δ 9.43 (dd, 429.2 (2-pyridin-3-yl-pyrimidin-5-yl)-1,3- 1H), 9.13 (s, 2H), 8.65 (dd, 1H), 8.58 diazaspiro[4.5]decan-2-one (dt, 1H), 7.52 (ddd, 1H), 7.42-7.36 (m, 4H), 7.28 (ddd, 1H), 3.72 (s, 2H), 1.98 (s, 6H), 2.02-1.89 (m, 4H), 1.57-1.46 (m, 4H). SC_3139 cis-5-(8-Dimethylamino-2-oxo-8- INT-991 2-aminoethanol SC_3133 1H NMR (600 MHz, DMSO) δ 9.08 (s, 2H), 439.3 phenyl-1,3-diazaspiro[4.5]decan-3- 8.59 (t, 1H), 7.94 (s, 1H), 7.43-7.30 (m, yl)-N-(2-hydroxy-ethyl)- 5H), 7.30-7.21 (m, 1H), 3.72 (s, 2H), 3.51 pyrimidine-2-carboxylic acid amide (q, 2H), 2.49-2.37 (m, 2H), 2.00-1.90 (m, 10H), 1.89-1.74 (m, 2H), 1.57-1.48 (m, 2H), 1.38-1.32 (m, 1H). SC_3141 cis-8-Dimethylamino-3-[2- INT-976 4-[5-bromo-4- SC_3103 1H NMR (600 MHz, DMSO) δ 8.59 (d, 1H), 505.3 morpholin-4-yl-4-(trifluoromethyl)- (trifluoromethyl)pyrmidin-2- 7.39-7.35 (m, 5H), 7.27 (d, 1H), 3.73 (t, pyrimidin-5-yl]-8-phenyl-1,3- yl]morpholine 4H), 3.67 (q, 4H), 3.28-3.22 (m, 1H), 2.41- diazaspiro[4.5]decan-2-one 2.28 (m, 2H), 1.98 (s, 6H), 1.94-1.80 (m, 3H), 1.53-1.42 (m, 2H). SC_3142 cis-4-[5-(8-Dimethylamino-2-oxo- INT-989 4-cyanophenylboronic acid SC_3129 1H NMR (600 MHz, DMSO) δ 9.15 (s, 2H), 453.2 8-phenyl-1,3-diazaspiro[4.5]decan- 8.49-8.43 (m, 2H), 7.99-7.92 (m, 2H), 3-yl)-pyrimidin-2-yl]-benzonitrile 7.89 (s, 1H), 7.38 (m, 4H), 7.28 (td, 1H), 3.73 (s, 2H), 2.48-2.35 (m, 1H), 2.03-1.90 (m, 10H), 1.55-1.48 (m, 2H). SC_3143 cis-5-(8-Ethylamino-2-oxo-8- INT-1008 5-Bromo-4-methoxy-pyrimidine-2- SC_3103 (DMSO-d6, 400 MHz), δ (ppm) = 8.79 (s, 407.2 phenyl-1,3-diazaspiro[4.5]decan-3- carbonitrile 1H), 7.60 (s, 1H), 7.41 (d, 2H, J = 7.72 Hz), yl)-4-methoxy-pyrimidine-2- 7.28 (t, 2H, J = 7.54 Hz), 7.16 (t, 1H, J = carbonitrile 7.32 Hz), 3.97 (s, 3H), 3.72 (s, 2H), 2.02 (bs, 4H), 1.90-1.69 (m, 5H), 1.51-1.48 (m, 2H), 0.89 (t, 3H, J = 6.56 Hz). SC_3144 trans-5-(8-Ethylamino-2-oxo-8- INT-1009 5-Bromo-4-methoxy-pyrimidine-2- SC_3103 1HNMR (DMSO-d6, 400 MHz), δ (ppm) = 407.3 phenyl-1,3-diazaspiro[4.5]decan-3- carbonitrile 8.87 (s, 1H), 8.10 (bs, 1H), 7.50 (d, 2H, J = yl)-4-methoxy-pyrimidine-2- 7.52 Hz), 7.31 (t, 2H, J = 7.20 Hz), 7.18 (t, carbonitrile 1H, J = 6.88 Hz), 4.04 (s, 3H), 3.74 (s, 2H), 2.07-1.95 (m, 6H), 1.70-1.54 (m, 4H), 0.93 (t, 3H, J = 6.62 Hz). SC_3145 cis-8-Dimethylamino-3-[2- INT-991 morpholine SC_3133 1H NMR (600 MHz, DMSO) δ 9.04 (s, 2H), 478.3 (morpholine-4-carbonyl)- 7.88 (s, 1H), 7.42-7.30 (m, 5H), 7.30- pyrimidin-5-yl]-8-phenyl-1,3- 7.22 (m, 1H), 3.75-3.58 (m, 6H), 3.51 (t, diazaspiro[4.5]decan-2-one 2H), 3.20 (t, 2H), 2.50-2.33 (m, 2H), 1.99- 1.90 (m, 8H), 1.89-1.74 (m, 2H), 1.54- 1.44 (m, 2H). SC_3147 cis-8-Dimethylamino-3-[2- INT-976 1-bromo-2- SC_3103 1H NMR (600 MHz, DMSO) δ 7.47 (d, 1H), 442.2 (methylsulfonyl-methyl)-phenyl]-8- (methylsulfonylmethyl)benzene 7.42-7.31 (m, 6H), 7.30-7.22 (m, 3H), phenyl-1,3-diazaspiro[4.5]decan-2- 4.50 (s, 2H), 3.56 (s, 2H), 2.88 (s, 3H), 2.42- one 2.28 (m, 2H), 2.07 (s, 2H), 1.98-1.90 (m, 8H), 1.89-1.69 (m, 2H), 1.61-1.48 (d, 2H). SC_3148 cis-8-Dimethylamino-3-(4-methyl- INT-992 morpholine SC_3120 1H NMR (600 MHz, DMSO) δ 8.14 (s, 1H), 451.3 2-morpholin-4-yl-pyrimidin-5-yl)- 7.40-7.32 (m, 4H), 7.26 (td, 1H), 7.21 (s, 8-phenyl-1,3-diazaspiro[4.5]decan- 1H), 3.69-3.60 (m, 8H), 3.38 (s, 2H), 2.41- 2-one 2.27 (m, 2H), 2.20 (s, 3H), 1.97 (s, 6H), 1.95- 1.76 (m, 4H), 1.54-1.45 (s, 2H). SC_3149 cis-8-Dimethylamino-3-[2-(1,1- INT-989 thiomorpholine-1,1-dioxide SC_3120 1H NMR (600 MHz, DMSO) δ 8.63 (s, 2H), 485.2 dioxo-[1,4]thiazinan-4-yl)- hydrochloride 7.50 (br s, 1H), 7.41-7.33 (m, 4H), 7.27 (td, pyrimidin-5-yl]-8-phenyl-1,3- 1H), 4.17-4.12 (m, 4H), 3.55 (s, 2H), 3.12- diazaspiro[4.5]decan-2-one 3.06 (m, 4H), 2.47-2.27 (m, 2H), 2.04- 1.74 (m, 10H), 1.51-1.42 (m, 2H). SC_3150 cis-8-Dimethylamino-3-(4-fluoro- INT-976 3-bromo-4-fluoro-pyridine SC_3103 1H NMR (600 MHz, DMSO) δ 8.70 (d, 1H), 369.2 pyridin-3-yl)-8-phenyl-1,3- 8.36 (dd, 1H), 7.54 (s, 1H), 7.36 (td, 5H), diazaspiro[4.5]decan-2-one 7.26 (s, 1H), 3.61 (s, 2H), 2.44-2.28 (m, 2H), 2.01-1.74 (m, 10H), 1.92 (d, 2H), 1.56- 1.45 (m, 2H). SC_3151 cis-5-(8-Dimethylamino-2-oxo-8- INT-991 2-(methylamino)ethanol SC_3133 1H NMR (600 MHz, DMSO) δ 9.03 (d, 2H), 453.2 phenyl-1,3-diazaspiro[4.5]decan-3- 7.86 (s, 1H), 7.40-7.23 (m, 5H), 3.69 (s, yl)-N-(2-hydroxy-ethyl)-N-methyl- 2H), 3.61 (q, 1H), 3.50 (t, 1H), 3.45 (d, 1H), pyrimidine-2-carboxylic acid amide 3.17 (t, 1H), 3.01 and 2.83 (both s, together 3H, amide rotamers), 2.49-2.36 (m, 2H), 2.00-1.89 (m, 8H), 1.89-1.73 (m, 2H), 1.55-1.47 (m, 2H). SC_3152 cis-5-(8-Dimethylamino-2-oxo-8- INT-976 5-bromo-2-morpholino-pyridine- SC_3103 1H NMR (600 MHz, DMSO) δ 8.24 (s, 1H), 461.3 phenyl-1,3-diazaspiro[4.5]decan-3- 4-carbonitrile 7.67-7.30 (m, 5H), 7.29 (s, 1H), 3.70-3.65 yl)-2-morpholin-4-yl- (m, 4H), 3.51-3.44 (m, 4H), 2.37-2.22 (m, isonicotinonitrile 2H), 2.10-1.87 (m, 10H), 1.53-1.31 (m, 2H). SC_3153 cis-4-(8-Dimethylamino-2-oxo-8- SC_3272 SC_3016 1H NMR (600 MHz, DMSO) δ 7.79 (d, 2H), 393.2 phenyl-1,3-diazaspiro[4.5]decan-3- 7.62 (d, 2H), 7.41-7.34 (m, 4H), 7.27 (td, yl)-benzamide 1H), 7.13-7.09 (m, 1H), 3.62 (s, 2H), 2.46- 2.35 (m, 2H), 1.97 (s, 6H), 1.93-1.76 (m, 4H), 1.51-1.45 (m, 2H). SC_3154 cis-8-Dimethylamino-3-(2-fluoro- INT-976 1-bromo-2-fluoro-4- SC_3103 1H NMR (600 MHz, DMSO) δ 7.89-7.83 446.2 4-methylsulfonyl-phenyl)-8- methylsulfonyl- (m, 1H), 7.76 (dd, 1H), 7.70 (dd, 1H), 7.40- phenyl-1,3-diazaspiro[4.5]decan-2- benzene 7.32 (m, 5H), 7.29-7.23 (m, 1H), 3.69 (s, one 2H), 3.23 (s, 3H), 2.43-2.30 (m, 2H), 1.96 (s, 6H), 1.94-1.88 (m, 2H), 1.53-1.47 (m, 2H). SC_3155 cis-4-(8-Dimethylamino-2-oxo-8- INT-976 4-bromo-3-fluoro-benzonitrile SC_3103 1H NMR (600 MHz, DMSO) δ 7.85-7.79 393.2 phenyl-1,3-diazaspiro[4.5]decan-3- (m, 2H), 7.73 (s, 1H), 7.62 (dd, 1H), 7.40- yl)-3-fluoro-benzonitrile 7.31 (m, 4H), 7.26 (tt, 1H), 3.69 (s, 2H), 2.40- 2.31 (m, 2H), 1.95 (s, 6H), 1.94-1.87 (m, 2H), 1.87-1.75 (m, 2H), 1.52-1.46 (m, 2H). SC_3156 cis-4-(8-Dimethylamino-2-oxo-8- INT-976 4-bromo-3,5-difluoro- SC_3103 1H NMR (600 MHz, DMSO) δ 7.85 (d, 2H), 411.2 phenyl-1,3-diazaspiro[4.5]decan-3- benzonitrile 7.61 (s, 1H), 7.39-7.31 (m, 4H), 7.25 (tt, yl)-3,5-difluoro-benzonitrile 1H), 3.53 (s, 2H), 2.42-2.33 (m, 2H), 1.98- 1.89 (m, 8H), 1.82-1.78 (m, 2H), 1.54- 1.47 (m, 2H). SC_3157 cis-8-Dimethylamino-3-(2- INT-989 methanol instead of SC_3120 1H NMR (600 MHz, DMSO) δ 8.76 (s, 2H), 382.2 methoxy-pyrimidin-5-yl)-8-phenyl- n-butanol as a solvent 7.41-7.33 (m, 5H), 7.27 (ddt, 1H), 3.86 (s, 1,3-diazaspiro[4.5]decan-2-one 3H), 3.60 (s, 2H), 2.47-2.30 (m, 2H), 2.01- 1.74 (m, 10H), 1.52-1.45 (m, 2H). SC_3158 cis-3-[2-(Benzylamino)-pyrimidin- INT-989 benzylamine SC_3120 1H NMR (600 MHz, DMSO) δ 8.43 (s, 2H), 457.3 5-yl]-8-dimethylamino-8-phenyl- 7.50-7.45 (m, 1H), 7.46-7.33 (m, 5H), 1,3-diazaspiro[4.5]decan-2-one 7.31-7.23 (m, 4H), 7.19 (tq, 1H), 4.46 (d, 2H), 4.02 (s, 1H), 3.50 (s, 2H), 2.41-2.31 (m, 2H), 1.97 (s, 6H), 1.88 (s, 2H), 1.49- 1.41 (m, 2H). SC_3159 cis-8-Dimethylamino-3-[2-(4- INT-989 (4-fluorophenyl)boronic acid SC_3129 1H NMR (600 MHz, DMSO) δ 9.07 (s, 2H), 446.2 fluorophenyl)-pyrimidin-5-yl]-8- 8.37-8.30 (m, 2H), 7.83 (s, 1H), 7.44- phenyl-1,3-diazaspiro[4.5]decan-2- 7.35 (m, 4H), 7.34-7.25 (m, 3H), 3.69 (s, one 2H), 2.47-2.30 (m, 2H), 2.08-1.80 (m, 10H), 1.55-1.46 (m, 2H). SC_3160 trans-8-Benzyl-8-dimethylamino-3- INT-995 4-(5-bromopyrimidin- SC_3103 1H NMR (600 MHz, DMSO) δ 8.57 (s, 2H), 451.3 (2-morpholin-4-yl-pyrimidin-5-yl)- 2-yl)morpholine 7.60 (s, 1H), 7.27 (t, 2H), 7.22-7.15 (m, 1,3-diazaspiro[4.5]decan-2-one 3H), 3.68-3.62 (m, 4H), 3.64-3.57 (m, 4H), 3.49 (s, 2H), 2.66 (s, 2H), 2.22 (s, 6H), 1.80-1.70 (m, 4H), 1.51-1.43 (m, 4H). SC_3161 cis-8-Benzyl-8-dimethylamino-3- INT-994 4-(5-bromopyrimidin- SC_3103 1H NMR (600 MHz, DMSO) δ 8.45 (s, 2H), 451.3 (2-morpholin-4-yl-pyrimidin-5-yl)- 2-yl)morpholine 7.27 (t, 2H), 7.22-7.15 (m, 3H), 7.11 (s, 1,3-diazaspiro[4.5]decan-2-one 1H), 3.68-3.56 (m, 8H), 2.64 (s, 2H), 2.26 (s, 6H), 1.87-1.77 (m, 4H), 1.42 (d, 2H), 1.15 (dt, 2H). SC_3163 cis-4-(8-Dimethylamino-2-oxo-8- SC_3156 SC_3016 1H NMR (600 MHz, DMSO) δ 8.08 (s, 1H), 429.2 phenyl-1,3-diazaspiro[4.5]decan-3- 7.65-7.58 (m, 2H), 7.48 (br s, 1H), 7.39- yl)-3,5-difluoro-benzamide 7.31 (m, 4H), 7.28-7.22 (m, 1H), 3.49 (s, 2H), 2.40-2.32 (m, 2H), 1.96 (s, 6H), 1.95- 1.90 (m, 2H), 1.87-1.77 (m, 2H), 1.54- 1.49 (m, 2H). SC_3164 cis-4-(8-Dimethylamino-2-oxo-8- SC_3155 SC_3016 1H NMR (600 MHz, DMSO) δ 7.95 (s, 1H), 411.2 phenyl-1,3-diazaspiro[4.5]decan-3- 7.72-7.64 (m, 2H), 7.61 (t, 1H), 7.54-7.50 yl)-3-fluoro-benzamide (m, 1H), 7.40-7.32 (m, 5H), 7.26 (tt, 1H), 3.62 (s, 2H), 2.41-2.31 (m, 2H), 1.96 (s, 6H), 1.93-1.88 (m, 2H), 1.86-1.75 (m, 2H), 1.53-1.45 (m, 2H). SC_3165 cis-8-Benzyl-8-dimethylamino-3- INT-994 5-bromo-2- SC_3103 1H NMR (600 MHz, DMSO) δ 9.07 (s, 2H), 434.2 [2-(trifluoromethyl)-pyrimidin-5- (trifluoromethyl)pyrimidine 7.77 (s, 1H), 7.29 (t, 2H), 7.24-7.17 (m, yl]-1,3-diazaspiro[4.5]decan-2-one 3H), 3.55 (s, 2H), 2.66 (s, 2H), 2.26 (s, 6H), 1.86 (dt, 4H), 1.44 (d, 2H), 1.25-1.17 (m, 2H). SC_3166 trans-8-Benzyl-8-dimethylamino-3- INT-995 5-bromo-2- SC_3103 1H NMR (600 MHz, DMSO) δ 9.16 (s, 2H), 434.2 [2-(trifluoromethyl)-pyrimidin-5- (trifluoromethyl)pyrimidine 8.28 (s, 1H), 7.27 (t, 2H), 7.22-7.16 (m, yl]-1,3-diazaspiro[4.5]decan-2-one 3H), 3.67 (s, 2H), 2.66 (s, 2H), 2.24 (s, 6H), 1.84-1.72 (m, 4H), 1.49 (q, 4H). SC_3167 cis-8-Dimethylamino-8-thiophen-2- INT-997 5-bromo-2- SC_3103 1H NMR (600 MHz, DMSO) δ 9.19 (d, 2H), 426.1 yl-3-[2-(trifluoromethyl)- (trifluoromethyl)pyrimidine 7.97 (s, 1H), 7.43 (t, 1H), 7.07 (dd, 1H), 6.97 pyrimidin-5-yl]-1,3- (d, 1H), 3.78 (s, 2H), 2.40-2.27 (m, 2H), diazaspiro[4.5]decan-2-one 2.04 (s, 6H), 1.96 (t, 2H), 1.90-1.79 (m, 2H), 1.60-1.52 (m, 2H). SC_3168 trans-8-Dimethylamino-8-thiophen- INT-998 5-bromo-2- SC_3103 1H NMR (600 MHz, DMSO) δ 9.20 (s, 2H), 426.1 2-yl-3-[2-(trifluoromethyl)- (trifluoromethyl)pyrimidine 8.00 (s, 1H), 7.45 (dd, 1H), 7.09 (dd, 1H), pyrimidin-5-yl]-1,3- 7.02-6.97 (m, 1H), 3.81 (s, 2H), 2.12 (d, diazaspiro[4.5]decan-2-one 4H), 2.03 (s, 6H), 1.85 (t, 2H), 1.62-1.54 (m, 2H). SC_3170 cis-8-Dimethylamino-8-phenyl-3- INT-989 piperidine SC_3120 1H NMR (DMSO-d6): δ 8.49 (s, 2H), 7.39- 435.3 (2-piperidin-1-yl-pyrimidin-5-yl)- 7.24 (m, 6H), 3.65-3.63 (m, 4H), 3.50 (s, 1,3-diazaspiro[4.5]decan-2-one 2H), 2.36-2.32 (m, 2H), 1.95-1.86 (m, 10H), 1.61-1.56 (m, 2H), 1.50-1.44 (m, 6H). SC_3171 cis-8-Dimethylamino-8-phenyl-3- INT-989 pyrrolidine SC_3120 1H NMR (CDCl3): δ 8.43 (s, 2H), 7.41-7.38 421.3 (2-pyrrolidin-1-yl-pyrimidin-5-yl)- (m, 2H), 7.32-7.30 (m, 3H), 5.05 (br s, 1H), 1,3-diazaspiro[4.5]decan-2-one 3.53 (t, 4H), 3.45 (s, 2H), 2.30-2.06 (m, 10H), 1.99-1.96 (m, 6H), 1.62-1.58 (m, 2H). SC_3172 cis-8-Dimethylamino-8-phenyl-3- INT-989 pyrimidin-5-ylboronic acid SC_3129 1H NMR (600 MHz, DMF) δ 9.56 (s, 2H), 430.2 (2-pyrimidin-5-yl-pyrimidin-5-yl)- 9.27 (s, 1H), 9.17 (s, 2H), 8.35 (s, 1H), 7.89 1,3-diazaspiro[4.5]decan-2-one (d, 2H), 7.63 (dq, 3H), 3.73 (s, 2H), 3.04 (d, 2H), 2.81 (s, 6H), 2.57 (td, 2H), 2.06 (d, 2H), 1.58 (td, 2H). SC_3174 trans-8-Benzyl-8-dimethylamino-3- INT-995 5-bromo-4-methyl-2- SC_3103 1H NMR (600 MHz, DMSO) δ 8.57 (s, 1H), 447.2 [4-methyl-6-(trifluoromethyl)- (trifluoromethyl)pyridine 7.80 (s, 1H), 7.67 (s, 1H), 7.27 (t, 2H), 7.23- pyridin-3-yl]-1,3- 7.15 (m, 3H), 3.58 (d, 2H), 2.67 (s, 2H), diazaspiro[4.5]decan-2-one 2.31 (s, 3H), 2.22 (d, 6H), 1.82-1.72 (m, 4H), 1.56 (dd, 2H), 1.48 (td, 2H). SC_3175 cis-5-(8-Dimethylamino-2-oxo-8- SC_3152 SC_3016 480.6 phenyl-1,3-diazaspiro[4.5]decan-3- yl)-2-morpholin-4-yl-pyridine-4- carboxylic acid amide SC_3176 cis-8-Dimethylamino-3-[2-(3,5- INT-989 (3,5-dimethylisoxazol-4- SC_3129 1H NMR (600 MHz, DMSO) δ 9.05 (s, 2H), 447.2 dimethyl-isoxazol-4-yl)-pyrimidin- yl)boronic acid 7.80 (s, 1H), 7.43-7.34 (m, 4H), 7.28 (tt, 5-yl]-8-phenyl-1,3- 1H), 3.68 (s, 2H), 2.69 (s, 3H), 2.47 (s, 3H), diazaspiro[4.5]decan-2-one 2.43-2.35 (m, 2H), 2.01-1.79 (m, 10H), 1.50 (s, 2H). SC_3177 cis-3-[2-(Benzothiazol-6-yl)- INT-989 1,3-benzothiazol-6- SC_3129 1H NMR (600 MHz, DMSO) δ 9.46 (s, 1H), 485.2 pyrimidin-5-yl]-8-dimethylamino- ylboronic acid 9.12 (s, 2H), 9.07 (s, 1H), 8.49 (d, 1H), 8.16 8-phenyl-1,3-diazaspiro[4.5]decan- (d, 1H), 7.84 (s, 1H), 7.39 (d, 4H), 7.29 (d, 2-one 1H), 3.73 (s, 2H), 2.42 (d, 2H), 1.97 (d, 10H), 1.54 (d, 2H). SC_3178 cis-8-Dimethylamino-3-[2-fluoro- INT-976 1-bromo-2-fluoro-4- SC_3103 1H NMR (600 MHz, DMSO) δ 7.80 (t, 1H), 436.2 4-(trifluoromethyl)-phenyl]-8- (trifluoromethyl)benzene 7.65 (dd, 1H), 7.53 (dd, 1H), 7.40-7.32 (m, phenyl-1,3-diazaspiro[4.5]decan-2- 4H), 7.29-7.23 (m, 1H), 3.66 (s, 2H), 2.36 one (s, 2H), 1.97-1.88 (m, 8H), 1.85-1.75 (m, 2H), 1.53-1.46 (m, 2H). SC_3179 cis-8-Dimethylamino-3-(6- INT-976 4-(5-bromo-2- as SC_3097 step 2 1H NMR (600 MHz, DMSO) δ 8.20 (d, 1H), 436.3 morpholin-4-yl-pyridin-3-yl)-8- pyridyl)morpholine 7.89 (dd, 1H), 7.37 (p, 5H), 7.27 (d, 1H), phenyl-1,3-diazaspiro[4.5]decan-2- 6.79 (d, 1H), 3.71-3.66 (m, 4H), 3.53 (s, one 2H), 2.43-2.32 (m, 2H), 1.96 (s, 7H), 1.91- 1.85 (m, 5H), 1.49-1.42 (m, 2H). SC_3180 cis-8-Dimethylamino-8-phenyl-3- INT-976 4-bromo-2-phenylthiazole SC_3103 1H NMR (DMSO-d6): δ 7.89-7.87 (m, 2H), 433.2 (2-phenyl-thiazol-4-yl)-1,3- 7.55 (br s, 1H), 7.43-7.35 (m, 8H), 7.29-7.26 diazaspiro[4.5]decan-2-one (m, 1H), 3.82 (s, 2H), 2.45 (br m, 2H), 1.96- 1.79 (m, 10H), 1.53-1.50 (m, 2H). SC_3181 cis-8-Dimethylamino-8-phenyl-3- INT-989 tetrahydro-2H-pyran-4-amine SC_3103 1H NMR (DMSO-d6): δ 8.42 (s, 2H), 7.39- 451.3 [2-(tetrahydro-pyran-4-ylamino)- 7.35 (m, 5H), 7.27-7.24 (m, 1H), 6.83 (d, pyrimidin-5-yl]-1,3- 1H), 3.84-3.79 (m, 3H), 3.50 (s, 2H), 3.38- diazaspiro[4.5]decan-2-one 3.35 (m, 2H), 2.36-2.32 (m, 2H), 1.94-1.77 (m, 12H), 1.50-1.40 (m, 4H). SC_3183 cis-8-Dimethylamino-8-phenyl-3- INT-976 2-bromo-4-phenylthiazole SC_3103 1H NMR (DMSO-d6): δ 8.09 (br s, 1H), 433.2 (4-phenyl-thiazol-2-yl)-1,3- 7.87 (d, 2H), 7.51 (s, 1H), 7.37-7.24 (m, 8H), diazaspiro[4.5]decan-2-one 3.87 (s, 2H), 2.43 (m, 2H), 1.96-1.84 (m, 10H), 1.54 (m, 2H). SC_3184 cis-8-Dimethylamino-8-phenyl-3- INT-976 1H-pyrrolo[2,3-b]pyridine SC_3103 1H NMR (DMSO-d6): δ 9.07 (s, 2H), 8.35- 468.2 [2-(1H-pyrrolo[2,3-b]pyridin-1-yl)- 8.33 (m, 1H), 8.10-8.04 (m, 2H), 7.83 (br s, pyrimidin-5-yl]-1,3- 1H), 7.41-7.37 (m, 4H), 7.29-7.21 (m, 2H), diazaspiro[4.5]decan-2-one 6.72-6.71 (d, 1H), 3.71 (s, 2H), 2.49 (m, 2H), 1.97 (m, 10H), 1.52 (m, 2H). SC_3185 cis-8-Dimethylamino-8-phenyl-3- INT-989 (3,4,5-trifluorophenyl)boronic SC_3129 1H NMR (600 MHz, DMSO) δ 9.11 (s, 2H), 481.2 [2-(3,4,5-trifluoro-phenyl)- acid 8.12-8.03 (m, 2H), 7.89 (s, 1H), 7.42- pyrimidin-5-yl]-1,3- 7.34 (m, 4H), 7.28 (dq, 1H), 3.71 (s, 2H), diazaspiro[4.5]decan-2-one 2.48-2.35 (m, 2H), 1.99-1.79 (m, 10H), 1.58-1.47 (m, 2H). SC_3187 cis-8-Dimethylamino-3-m-tolyl-8- INT-976 1-bromo-3-methylbenzene SC_3186 363.2 phenyl-1,3-diazaspiro[4.5]decan-2- one SC_3188 cis-8-Dimethylamino-8-phenyl-3-p- INT-976 1-bromo-4-methylbenzene SC_3186 363.2 tolyl-1,3-diazaspiro[4.5]decan-2- one SC_3189 cis-8-Dimethylamino-8-phenyl-3- INT-976 1-bromo-4- SC_3186 417.2 [4-(trifluoromethyl)-phenyl]-1,3- trifluoromethylbenzene diazaspiro[4.5]decan-2-one SC_3190 cis-8-Dimethylamino-8-phenyl-3- INT-976 1-bromo-3- SC_3186 433.2 [3-(trifluoromethyloxy)-phenyl]- (trifluoromethoxy)benzene 1,3-diazaspiro[4.5]decan-2-one SC_3191 cis-8-Dimethylamino-8-phenyl-3- INT-976 1-bromo-4- SC_3186 433.2 [4-(trifluoromethyloxy)-phenyl]- (trifluoromethoxy)benzene 1,3-diazaspiro[4.5]decan-2-one SC_3192 cis-2-(8-Dimethylamino-2-oxo-8- INT-976 methyl 2-bromobenzoate SC_3186 407.2 phenyl-1,3-diazaspiro[4.5]decan-3- yl)-benzoic acid methyl ester SC_3193 cis-3-(8-Dimethylamino-2-oxo-8- INT-976 methyl 3-bromobenzoate SC_3186 407.2 phenyl-1,3-diazaspiro[4.5]decan-3- yl)-benzoic acid methyl ester SC_3194 cis-4-(8-Dimethylamino-2-oxo-8- INT-976 methyl 4-bromobenzoate SC_3186 407.2 phenyl-1,3-diazaspiro[4.5]decan-3- yl)-benzoic acid methyl ester SC_3195 cis-3-(1,3-Benzodioxol-5-yl)-8- INT-976 5-bromobenzo[d][1,3]dioxole SC_3186 393.2 dimethylamino-8-phenyl-1,3- diazaspiro[4.5]decan-2-one SC_3196 cis-8-Dimethylamino-8-phenyl-3- INT-976 5-bromoquinoline SC_3186 400.2 quinolin-5-yl-1,3- diazaspiro[4.5]decan-2-one SC_3197 cis-3-(2,3-Dihydro-1H-indol-6-yl)- INT-976 6-bromoindoline SC_3186 390.2 8-dimethylamino-8-phenyl-1,3- diazaspiro[4.5]decan-2-one SC_3198 cis-5-(8-Dimethylamino-2-oxo-8- INT-976 methyl 5-bromo-4- SC_3186 422.2 phenyl-1,3-diazaspiro[4.5]decan-3- methylpicolinate yl)-4-methyl-pyridine-2-carboxylic acid methyl ester SC_3199 cis-8-Dimethylamino-3-(6- INT-976 5-bromo-2-methoxy- SC_3186 394.2 methoxy-4-methyl-pyridin-3-yl)-8- 4-methylpyridine phenyl-1,3-diazaspiro[4.5]decan-2- one SC_3200 cis-8-Dimethylamino-3-[2-methyl- INT-976 5-bromo-1-methyl-3- SC_3186 421.2 5-(trifluoromethyl)-2H-pyrazol-3- (trifluoromethyl)-1H-pyrazole yl]-8-phenyl-1,3- diazaspiro[4.5]decan-2-one SC_3201 cis-8-Dimethylamino-3-(3- INT-976 2-bromo-3-methoxypyridine SC_3186 380.2 methoxy-pyridin-2-yl)-8-phenyl- 1,3-diazaspiro[4.5]decan-2-one SC_3202 cis-8-Dimethylamino-8-phenyl-3- INT-976 2-bromo-5- SC_3186 418.2 [5-(trifluoromethyl)-pyridin-2-yl]- trifluoromethylpyridine 1,3-diazaspiro[4.5]decan-2-one SC_3203 cis-5-(8-Dimethylamino-2-oxo-8- INT-976 3-bromo-5-cyanopyridine SC_3186 375.2 phenyl-1,3-diazaspiro[4.5]decan-3- yl)-nicotinonitrile SC_3204 cis-8-Dimethylamino-3-(3-methyl- INT-976 2-bromo-3-methylpyridine SC_3186 364.2 pyridin-2-yl)-8-phenyl-1,3- diazaspiro[4.5]decan-2-one SC_3205 cis-8-Dimethylamino-3-(6- INT-976 5-bromo-2-methoxypyridine SC_3186 380.2 methoxy-pyridin-3-yl)-8-phenyl- 1,3-diazaspiro[4.5]decan-2-one SC_3206 cis-8-Dimethylamino-8-phenyl-3- INT-976 1-bromo-3- SC_3186 417.2 [3-(trifluoromethyl)phenyl]-1,3- trifluoromethylbenzene diazaspiro[4.5]decan-2-one SC_3207 cis-3-(1,3-Benzodioxol-4-yl)-8- INT-976 4-bromobenzo[d][1,3]dioxole SC_3186 393.2 dimethylamino-8-phenyl-1,3- diazaspiro[4.5]decan-2-one SC_3209 cis-8-Dimethylamino-3-[2-(3,5- INT-976 3,5-dimethyl-1H-pyrazole SC_3103 1H NMR (DMSO-d6): δ 9.00 (s, 2H), 7.81 446.2 dimethyl-1H-pyrazol-1-yl)- (br s, 1H), 7.38-7.27 (m, 5H), 6.07 (s, 1H), pyrimidin-5-yl]-8-phenyl-1,3- 3.69 (s, 2H), 2.45 (m, 5H), 2.17 (s, 3H), diazaspiro[4.5]decan-2-one 1.96-1.91 (m, 10H), 1.51(br m, 2H). SC_3210 cis-8-Dimethylamino-3-[2-(3- INT-989 rac-piperidin-3-ol SC_3182 1H NMR (DMS0-d6): 8.48 (s, 2H), 7.39- 451.2 hydroxy-piperidin-1-yl)-pyrimidin- 7.35 (m, 5H), 7.27-7.24 (m, 1H), 4.82 (d, 5-yl]-8-phenyl-1,3- 1H), 4.39-4.36 (m, 1H), 4.24-4.21 (m, 1H), diazaspiro[4.5]decan-2-one 3.51 (s, 2H), 3.41-3.36 (m, 1H), 2.92-2.87 (m, 1H), 2.77-2.72 (m, 1H), 2.42-2.32 (m, 2H), 2.00-1.66 (m, 12H), 1.46-1.39 (m, 2H), 1.34 (t, 2H). SC_3211 cis-8-Dimethylamino-3-[2-(3- INT-989 rac-piperidin-3-ol SC_3182 1H NMR (DMSO-d6): 8.48 (s, 2H), 7.35 (m, 451.3 hydroxy-piperidin-1-yl)-pyrimidin- 5H), 7.25 (m, 1H), 4.82 (d, 1H), 4.39-4.37 5-yl]-8-phenyl-1,3- (m, 1H), 4.24-4.21 (m, 1H), 3.51 (s, 2H), diazaspiro[4.5]decan-2-one 3.40-3.39 (m, 1H), 2.90-2.87 (m, 1H), 2.77- 2.72 (m, 1H), 2.37 (m, 2H), 2.00-1.66 (m, 12H), 1.45 (m, 2H), 1.34 (t, 2H). SC_3212 cis-8-Dimethylamino-3-[2-[4-(2- INT-989 2-piperazin-1-ylethanol SC_3120 1H NMR (600 MHz, DMSO) δ 8.53 (s, 2H), 480.3 hydroxy-ethyl)-piperazin-1-yl]- 7.37 (p, 5H), 7.27 (d, 1H), 3.62 (t, 4H), 3.53 pyrimidin-5-yl]-8-phenyl-1,3- (q, 4H), 2.49-2.27 (m, 7H), 1.96 (s, 6H), diazaspiro[4.5]decan-2-one 1.94-1.73 (m, 4H), 1.51-1.40 (m, 2H). SC_3213 cis-2-[4-[5-(8-Dimethylamino-2- SC_3146 INT-991 1H NMR (600 MHz, DMSO) δ 8.53 (s, 2H), 494.3 oxo-8-phenyl-1,3- 7.57 (s, 1H), 7.42 (d, 4H), 7.33 (d, 1H), 3.68 diazaspiro[4.5]decan-3-yl)- (t, 4H), 3.19 (s, 2H), 2.62 (t, 4H), 2.37 (d, pyrimidin-2-yl]-piperazin-1-yl]- 2H), 2.20-1.96 (m, 8H), 1.88 (t, 2H), 1.43 acetic acid (t, 2H). SC_3214 cis-8-Dimethylamino-3-[2-(1- INT-989 1-methyl-4-(4,4,5,5- SC_3208 1H NMR (600 MHz, DMSO + 2 vol % TFA) 484.3 methyl-1H-pyrrolo[2,3-b]pyridin-4- tetramethyl-1,3,2- δ 9.85 (s, 1H), 9.13 (s, 2H), 8.41 (d, 2H), yl)-pyrimidin-5-yl]-8-phenyl-1,3- dioxaborolan-2-yl)- 7.99 (s, 1H), 7.72 (s, 2H), 7.66-7.46 (m, diazaspiro[4.5]decan-2-one 2,3-dihydropyrrolo[2,3- 4H), 7.30 (s, 1H), 3.88 (s, 2H), 3.60 (s, 6H), b]pyridine 2.77-2.71 (m, 2H), 2.30-2.26 (m, 2H), 1.94-1.89 (m, 2H), 1.75 (s, 3H), 1.41- 1.35 (m, 2H). SC_3215 cis-8-Benzyl-8-dimethylamino-3- INT-994 5-bromo-4-methyl-2- SC_3103 1H NMR (600 MHz, DMSO) δ 8.52 (s, 1H), 447.2 [4-methyl-6-(trifluoromethyl)- (trifluoromethyl)pyridine 7.76 (s, 1H), 7.23 (dd, 2H), 7.19-7.11 (m, pyridin-3-yl]-1,3- 4H), 2.62 (s, 2H), 2.27 (s, 6H), 2.25 (s, 3H), diazaspiro[4.5]decan-2-one 1.86 (td, 2H), 1.80 (dt, 2H), 1.57-1.49 (m, 2H), 1.09 (td, 2H). SC_3216 trans-8-Dimethylamino-3-[4- INT-998 5-bromo-4-methyl-2- SC_3103 1H NMR (600 MHz, DMSO) δ 8.61 (s, 1H), 439.2 methyl-6-(trifluoromethyl)-pyridin- (trifluoromethyl)pyridine 7.83 (s, 1H), 7.53-7.49 (m, 1H), 7.45 (dd, 3-yl]-8-thiophen-2-yl-1,3- 1H), 7.09 (dd, 1H), 6.99 (dd, 1H), 3.70 (s, diazaspiro[4.5]decan-2-one 2H), 2.35 (s, 3H), 2.19-2.05 (m, 4H), 2.02 (s, 6H), 1.93-1.85 (m, 2H), 1.64 (dt, 2H). SC_3217 cis-8-Dimethylamino-3-[4-methyl- INT-997 5-bromo-4-methyl-2- SC_3103 1H NMR (600 MHz, DMSO) δ 8.58 (s, 1H), 439.2 6-(trifluoromethyl)-pyridin-3-yl]-8- (trifluoromethyl)pyridine 7.80 (s, 1H), 7.45 (s, 1H), 7.42 (dd, 1H), thiophen-2-yl-1,3- 7.05 (dd, 1H), 6.95 (dd, 1H), 3.67 (s, 2H), diazaspiro[4.5]decan-2-one 2.33 (s, 3H), 2.32-2.25 (m, 2H), 2.04 (s, 6H), 2.00-1.92 (m, 2H), 1.89-1.76 (m, 2H), 1.62 (dt, 2H). SC_3218 cis-8-Dimethylamino-3-[2-(1,1- INT-976 4-[5-bromo-4- SC_3103 1H NMR (600 MHz, DMSO) δ 8.65 (s, 1H), 553.2 dioxo-[1,4]thiazinan-4-yl)-4- (trifluoromethyl)pyrimidin-2-yl]-1,4- 7.42 (s, 1H), 7.41-7.31 (m, 5H), 7.25 (tt, (trifluoromethyl)-pyrimidin-5-yl]- thiazinane 1,1- 1H), 4.23 (t, 4H), 3.22 (t, 4H), 2.40-2.26 8-phenyl-1,3-diazaspiro[4.5]decan- dioxide (prepared as SC_3097 step 1) (m, 2H), 1.97-1.88 (m, 8H), 1.87-1.75 2-one (m, 2H), 1.54-1.42 (m, 2H). SC_3219 cis-8-Dimethylamino-8-(1-methyl- INT-1000 5-bromo-2- SC_3103 1H NMR (600 MHz, DMSO) δ 9.14 (s, 2H), 474.2 1H-benzoimidazol-2-yl)-3-[2- (trifluoromethyl)pyrimidine 8.65 (s, 1H), 7.63 (d, 1H), 7.51 (d, 1H), 7.25 (trifluoromethyl)-pyrimidin-5-yl]- (ddd, 1H), 7.19 (ddd, 1H), 4.02 (s, 3H), 3.61 1,3-diazaspiro[4.5]decan-2-one (s, 2H), 2.26 (d, 2H), 2.18 (s, 6H), 2.16- 2.09 (m, 2H), 1.87 (s, 2H), 1.78 (d, 2H). SC_3220 cis-8-Dimethylamino-8-(1-methyl- INT-1000 5-bromo-4-methyl-2- SC_3103 1H NMR (600 MHz, DMSO) δ 8.56 (s, 1H), 487.3 1H-benzoimidazol-2-yl)-3-[4- (trifluoromethyl)pyridine 8.10 (s, 1H), 7.80 (s, 1H), 7.60 (d, 1H), 7.50 methyl-6-(trifluoromethyl)-pyridin- (d, 1H), 7.23 (ddd, 1H), 7.17 (td, 1H), 4.02 3-yl]-1,3-diazaspiro[4.5]decan-2- (s, 3H), 3.50 (s, 2H), 2.34-2.25 (m, 5H), one 2.19-2.09 (m, 8H), 1.90-1.74 (m, 4H). SC_3222 cis-3-[2-(Benzyl-methyl-amino)- INT-976 N-benzyl-5-bromo-N- SC_3103 1H NMR (DMSO-d6): δ 8.52 (s, 2H), 7.39- 471.2 pyrimidin-5-yl]-8-dimethylamino- methylpyrimidin-2-amine 7.33 (m, 5H), 7.30-7.17 (m, 6H), 4.81 (s, 8-phenyl-1,3-diazaspiro[4.5]decan- 2H), 3.52 (s, 2H), 3.03 (s, 3H), 2.45-2.32 (m, 2-one 2H), 1.95-1.86 (m, 10H), 1.47-1.43 (m, 2H). SC_3223 cis-5-(8-Dimethylamino-2-oxo-8- INT-976 ethyl 5-bromopyrimidine-2- SC_3103 (step 1), 1H NMR (DMSO-d6): δ 9.04 (s, 2H), 8.24- 585.3 phenyl-1,3-diazaspiro[4.5]decan-3- carboxylate (step 1), 2,5,8,11- INT-991 (step 2), 8.23 (m, 1H), 7.42-7.39 (m, 2H), 7.32-7.31 yl)-N-[2-[2-[2-(2-methoxy-ethoxy)- tetraoxatridecan-13-amine (step 3) SC_3133 (step 3) (m, 3H), 5.70 (s, 1H), 3.70-3.60 (m, 16H), ethoxy]-ethoxy]-ethyl]-pyrimidine- 3.54-3.52 (m, 2H), 3.35 (s, 3H), 2.21-2.00 2-carboxylic acid amide (m, 12H), 1.66-1.64 (m, 2H). SC_3225 cis-8-Dimethylamino-3-[2-[(2- INT-989 2-(methylamino)ethanol SC_3182 1H NMR (DMSO-d6): δ 8.46 (s, 2H), 7.39- 425.2 hydroxy-ethyl)-methyl-amino]- 7.33 (m, 5H), 7.27-7.24 (m, 1H), 4.62 (t, pyrimidin-5-yl]-8-phenyl-1,3- 1H), 3.61-3.50 (m, 6H), 3.08 (s, 3H), 2.36- diazaspiro[4.5]decan-2-one 2.33 (m, 2H), 1.95-1.86 (m, 10H), 1.47-1.45 (m, 2H). SC_3226 cis-3-(8-Dimethylamino-2-oxo-8- INT-976 5-bromo-4-methyl-2- SC_3103 (step 1), 487.3 phenyl-1,3-diazaspiro[4.5]decan-3- (trifluoromethyl)pyridine SC_3016 (step 2) yl)-benzamide SC_3227 cis-8-Dimethylamino-3-[3-fluoro- INT-976 2-bromo-3-fluoro-5- SC_3186 417.1 5-(trifluoromethyl)-pyridin-2-yl]-8- (trifluoromethyl)pyridine phenyl-1,3-diazaspiro[4.5]decan-2- one SC_3228 cis-8-Dimethylamino-3-(5-methyl- INT-976 2-bromo-5-methylpyrazine SC_3186 459.1 pyrazin-2-yl)-8-phenyl-1,3- diazaspiro[4.5]decan-2-one SC_3229 cis-8-Dimethylamino-3-(5-fluoro- INT-976 4-bromo-5-fluoropyrimidine SC_3186 433.2 pyrimidin-4-yl)-8-phenyl-1,3- diazaspiro[4.5]decan-2-one SC_3230 cis-8-Dimethylamino-3-(5-fluoro- INT-976 2-bromo-5-fluoropyrimidine SC_3186 458.1 pyrimidin-2-yl)-8-phenyl-1,3- diazaspiro[4.5]decan-2-one SC_3231 cis-8-Dimethylamino-8-phenyl-3- INT-976 2-bromopyrazine SC_3186 471.1 pyrazin-2-yl-1,3- diazaspiro[4.5]decan-2-one SC_3232 cis-3-([2,1,3]Benzoxadiazol-5-yl)- INT-976 5-bromobenzo[c][1,2,5]- SC_3186 444.1 8-dimethylamino-8-phenyl-1,3- oxadiazole diazaspiro[4.5]decan-2-one SC_3233 cis-2-[2-(8-Dimethylamino-2-oxo- SC_3169 ammonium chloride SC_3133 1H NMR (600 MHz, DMSO) δ 7.73 (s, 1H), 423.2 8-phenyl-1,3-diazaspiro[4.5]decan- 7.40-7.32 (m, 4H), 7.31 (s, 1H), 7.26 (dd, 3-yl)-phenoxy]-acetamide 1H), 7.18 (td, 1H), 6.98-6.91 (m, 2H), 4.50 (s, 2H), 3.52 (s, 2H), 2.42-2.29 (m, 2H), 2.01-1.71 (m, 10H), 1.55-1.48 (m, 2H). SC_3234 cis-8-Dimethylamino-8-phenyl-3- INT-976 4-(5-bromothiophen-2-yl)pyridine SC_3103 1H NMR (DMSO-d6): δ 8.45-8.43 (d, 2H), 433.2 (5-pyridin-4-yl-thiophen-2-yl)-1,3- 7.87 (br s, 1H), 7.54-7.53 (d, 1H), 7.49-7.48 diazaspiro[4.5]decan-2-one (m, 2H), 7.38-7.27 (m, 5H), 6.35-6.34 (d, 2H), 3.64 (s, 2H), 2.42 (m, 2H), 1.96-1.90 (m, 10H), 1.51-1.49 (m, 2H). SC_3236 cis-8-Dimethylamino-3-(2- INT-1002 morpholine SC_3120 1H NMR (600 MHz, DMSO) δ 8.07 (d, 1H), 437.3 morpholin-4-yl-pyrimidin-4-yl)-8- 7.93 (s, 1H), 7.37 (dt, 5H), 7.27 (t, 1H), 3.65 phenyl-1,3-diazaspiro[4.5]decan-2- (s, 2H), 3.58 (s, 8H), 2.40-2.27 (m, 2H), one 1.94 (s, 6H), 1.92-1.80 (m, 4H), 1.43 (d, 2H). SC_3237 cis-3-[2-(3,4-Difluoro-phenyl)- INT-989 (3,4-difluorophenyl)boronic acid SC_3129 1H NMR (600 MHz, DMSO) δ 9.08 (s, 2H), 463.2 pyrimidin-5-yl]-8-dimethylamino- 8.22-8.12 (m, 2H), 7.54 (dt, 1H), 7.41- 8-phenyl-1,3-diazaspiro[4.5]decan- 7.37 (m, 4H), 7.29 (s, 1H), 3.70 (s, 2H), 2.06- 2-one 1.75 (m, 12H), 1.50 (d, 2H). SC_3241 cis-2-[4-[5-(8-Dimethylamino-2- SC_3213 ammonium chloride SC_3133 1H NMR (600 MHz, DMSO) δ 8.53 (s, 2H), 493.3 oxo-8-phenyl-1,3- 7.38 (d, 5H), 7.27 (s, 1H), 7.23 (s, 1H), 7.11 diazaspiro[4.5]decan-3-yl)- (s, 1H), 3.67 (t, 4H), 3.54-3.50 (m, 2H), pyrimidin-2-yl]-piperazin-1-yl]- 2.89 (s, 2H), 2.47 (t, 4H), 2.39-2.35 (m, acetamide 2H), 1.96 (s, 7H), 1.93-1.82 (m, 3H), 1.48- 1.44 (m, 2H). SC_3243 cis-8-Dimethylamino-3-[6-(4- INT-976 1-(5-bromo-2-pyridyl)-4-methyl- SC_3242 (step 2) 1H NMR (600 MHz, DMSO) δ 8.16 (d, 1H), 449.3 methyl-piperazin-1-yl)-pyridin-3- piperazine 7.86 (dd, 1H), 7.41-7.33 (m, 4H), 7.32 (s, yl]-8-phenyl-1,3- 1H), 7.27 (t, 1H), 6.78 (d, 1H), 3.51 (s, 2H), diazaspiro[4.5]decan-2-one 2.55-2.45 (m, 4H), 2.42-2.27 (m, 6H), 2.21 (s, 3H), 1.96 (s, 6H), 1.93-1.73 (m, 4H), 1.46 (t, 2H). SC_3244 cis-8-Dimethylamino-3-[2-(1,1- INT-976 4-(5-bromo-4-methyl- SC_3103 1H NMR (600 MHz, DMSO) δ 8.20 (s, 1H), 499.3 dioxo-[1,4]thiazinan-4-yl)-4- pyrimidin-2-yl)-1,4- 7.36 (h, 4H), 7.30-7.17 (m, 2H), 4.23- methyl-pyrimidin-5-yl]-8-phenyl- thiazinane 1,1-dioxide 4.17 (m, 4H), 3.13 (t, 4H), 2.44-2.28 (m, 1,3-diazaspiro[4.5]decan-2-one 2H), 2.24 (s, 3H), 1.97 (s, 6H), 1.91 (d, 4H), 1.55-1.44 (m, 2H). SC_3245 cis-8-Dimethylamino-8-phenyl-3- INT-976 5-bromo-2-(trifluoromethyl)- SC_3103 1H NMR (600 MHz, DMSO) δ 9.17 (s, 2H), 419.2 [2-(trifluoromethyl)-pyrimidin-5- pyrimidine 8.03 (s, 1H), 7.38 (s, 4H), 7.28 (tt, 1H), 3.73 yl]-1,3-diazaspiro[4.5]decan-2-one (s, 2H), 2.49-2.35 (m, 2H), 1.97 (s, 6H), 1.97-1.92 (m, 2H), 1.90-1.73 (m, 2H), 1.55-1.49 (m, 2H). SC_3246 cis-2-[8-Dimethylamino-1-(3- INT-979 2-chloropyrimidine- SC_3103 1H NMR (600 MHz, DMSO) δ 9.02 (s, 2H), 449.3 methoxy-propyl)-2-oxo-8-phenyl- 5-carbonitrile 7.40-7.31 (m, 5H), 3.86 (s, 2H), 3.26 (s, 1,3-diazaspiro[4.5]decan-3-yl]- 3H), 3.29-3.19 (m, 2H), 2.73-2.67 (m, pyrimidine-5-carbonitrile 2H), 2.16 (td, 2H), 2.00 (s, 7H), 1.83 (dt, 2H), 1.50-1.40 (m, 5H). SC_3247 cis-8-Dimethylamino-3-[2-(4- INT-989 1-Methylpiperazin SC_3120 1H NMR (600 MHz, DMSO) δ 8.54 (s, 2H), 450.3 methyl-piperazin-1-yl)- 7.48-7.33 (m, 5H), 7.31-7.21 (m, 1H), pyrimidin-5-yl]-8-phenyl-1,3- 3.63 (dd, 4H), 2.45-2.29 (m, 6H), 2.20 (s, diazaspiro[4.5]decan-2-one 3H), 1.96 (s, 6H), 1.94-1.78 (m, 4H), 1.51- 1.42 (m, 2H). SC_3248 cis-8-Dimethylamino-1-[(1- SC_3245 [1-[tert-butyl(dimethyl)silyl]- INT-988 (step 1) 1H NMR (600 MHz, DMSO) δ 9.24 (s, 2H), 504.3 hydroxy-cyclobutyl)-methyl]-8- oxycyclobutyl]methyl 7.38 (d, 4H), 7.27 (p, 1H), 3.89 (s, 2H), 2.73- phenyl-3-[2-(trifluoromethyl)- 4-methylbenzenesulfonate 2.67 (m, 2H), 2.26 (ddd, 2H), 2.19 (tt, 2H), pyrimidin-5-yl]-1,3- 2.08 (s, 1H), 2.00 (s, 6H), 1.92 (qd, 2H), diazaspiro[4.5]decan-2-one 1.73-1.64 (m, 1H), 1.60-1.50 (m, 3H), 1.50-1.45 (m, 2H). SC_3249 cis-2-[1-(3-Methoxy-propyl)-8- SC_3246 SC_3099 1H NMR (600 MHz, DMSO) δ 9.05 (s, 2H), 435.3 methylamino-2-oxo-8-phenyl-1,3- 7.49-7.44 (m, 2H), 7.34 (t, 2H), 7.21 (t, diazaspiro[4.5]decan-3-yl]- 1H), 3.90 (s, 2H), 3.26 (s, 3H), 2.23 (td, 2H), pyrimidine-5-carbonitrile 2.07 (s, 1H), 1.91 (d, 5H), 1.86-1.78 (m, 2H), 1.73 (tt, 2H), 1.42 (d, 2H). SC_3250 cis-8-Dimethylamino-8-phenyl-3- INT-976 5-bromo-2- SC_3103 1H NMR (600 MHz, DMSO) δ 8.88 (d, 1H), 419.3 [6-(trifluoromethyl)-pyridin-3-yl]- (trifluoromethyl)pyridine 8.24 (dd, 1H), 7.86 (s, 1H), 7.78 (d, 1H), 1,3-diazaspiro[4.5]decan-2-one 7.41-7.34 (m, 4H), 7.27 (t, 1H), 3.69 (s, 2H), 2.42 (s, 2H), 1.97 (s, 6H), 1.96-1.74 (m, 4H), 1.53-1.47 (m, 2H). SC_3251 cis-5-(8-Dimethylamino-2-oxo-8- INT-976 5-bromopyridine-2-carbonitrile SC_3103 1H NMR (600 MHz, DMSO) δ 8.92 (d, 1H), 376.2 phenyl-1,3-diazaspiro[4.5]decan-3- 8.15 (dd, 1H), 7.95 (br s, 1H), 7.90 (d, 1H), yl)-pyridine-2-carbonitrile 7.41-7.34 (m, 4H), 7.27 (t, 1H), 3.69 (s, 2H), 2.44-2.40 (m, 2H), 1.97 (s, 6H), 1.96- 1.89 (m, 3H), 1.90-1.70 (m, 1H), 1.53- 1.46 (m, 2H). SC_3252 cis-8-Dimethylamino-3-(2- INT-989 morpholine SC_3120 1H NMR (600 MHz, DMSO) δ 8.57 (s, 2H), 437.3 morpholin-4-yl-pyrimidin-5-yl)-8- 7.46-7.42 (m, 1H), 7.40-7.34 (m, 4H), phenyl-1,3-diazaspiro[4.5]decan-2- 7.27 (td, 1H), 3.64 (dd, 4H), 3.59 (dd, 4H), one 3.54 (s, 2H), 2.46-2.29 (m, 2H), 1.96 (s, 7H), 1.93-1.73 (m, 3H), 1.50-1.44 (m, 2H). SC_3253 cis-8-Dimethylamino-3-(2-methyl- INT-976 5-bromo-2-methyl-pyrimidine SC_3103 1H NMR (600 MHz, DMSO) δ 8.86 (s, 2H), 366.3 pyrimidin-5-yl)-8-phenyl-1,3- 7.69 (s, 1H), 7.41-7.33 (m, 5H), 7.31- diazaspiro[4.5]decan-2-one 7.19 (m, 1H), 3.62 (s, 2H), 2.53 (s, 3H), 2.48- 2.31 (m, 2H), 1.97 (s, 6H), 1.95-1.77 (m, 4H), 1.52-1.46 (m, 2H). SC_3254 cis-8-Dimethylamino-1-[(2- SC_3253 2-methoxybenzyl bromide SC_3105 1H NMR (DMSO-d6): δ 8.90 (s, 2H), 7.39- 486.2 methoxyphenyl)-methyl]-3-(2- 7.34 (m, 3H), 7.28-7.22 (m, 4H), 6.95-6.87 methyl-pyrimidin-5-yl)-8-phenyl- (m, 2H), 4.58 (s, 2H), 3.89 (s, 3H), 3.63 (s, 1,3-diazaspiro[4.5]decan-2-one 2H), 2.68-2.64 (m, 5H), 2.35-2.28 (m, 2H), 2.01(s, 6H), 1.49-1.43 (m, 4H). SC_3255 cis-1-[(1-Hydroxy-cyclobutyl)- SC_3248 SC_3099 1H NMR (600 MHz, DMSO) δ 9.26 (s, 2H), 490.3 methyl]-8-methylamino-8-phenyl- 7.51 (d, 2H), 7.34 (t, 2H), 7.22 (t, 1H), 3.92 3-[2-(trifluoromethyl)-pyrimidin-5- (s, 2H), 3.41 (s, 1H), 2.31 (td, 2H), 2.15 (td, yl]-1,3-diazaspiro[4.5]decan-2-one 2H), 2.07 (d, 1H), 1.93 (d, 7H), 1.83 (dt, 2H), 1.67 (t, 1H), 1.56 (q, 1H), 1.47 (d, 2H). SC_3256 cis-8-Dimethylamino-1-[(1- SC_3253 [1-[tert-butyl(dimethyl)silyl]- INT-988 (step 1) 1H NMR (600 MHz, DMSO) δ 8.92 (s, 2H), 450.3 hydroxy-cyclobutyl)-methyl]-3-(2- oxycyclobutyl]methyl 7.37 (d, 4H), 7.27 (td, 1H), 3.79 (s, 2H), 3.27 methyl-pyrimidin-5-yl)-8-phenyl- 4-methylbenzenesulfonate (s, 1H), 2.72-2.65 (m, 2H), 2.54 (s, 3H), 1,3-diazaspiro[4.5]decan-2-one 2.25-2.19 (m, 2H), 2.16 (tt, 2H), 2.07 (s, 2H), 2.00 (s, 6H), 1.95-1.86 (m, 2H), 1.67 (qd, 1H), 1.55 (td, 2H), 1.51-1.42 (m, 3H). SC_3257 cis-1-[(1-Hydroxy-cyclobutyl)- SC_3260 SC_3099 1H NMR (600 MHz, DMSO) δ 9.07 (s, 2H), 422.3 methyl]-8-methylamino-8-phenyl- 8.81 (s, 1H), 7.53-7.48 (m, 2H), 7.33 (t, 3-pyrimidin-5-yl-1,3- 2H), 7.24-7.18 (m, 1H), 3.86 (s, 2H), 2.29 diazaspiro[4.5]decan-2-one (td, 2H), 2.14 (tt, 2H), 2.07 (s, 1H), 1.96- 1.87 (m, 8H), 1.82 (td, 2H), 1.71-1.62 (m, 1H), 1.54 (dp, 1H), 1.49-1.43 (m, 2H). SC_3258 cis-5-(8-Dimethylamino-2-oxo-8- INT-976 5-bromo-4-methyl-pyridine-2- SC_3103 1H NMR (600 MHz, DMSO) δ 8.57 (s, 1H), 390.2 phenyl-1,3-diazaspiro[4.5]decan-3- carbonitrile 7.92 (s, 1H), 7.61-7.57 (m, 1H), 7.42- yl)-4-methyl-pyridine-2- 7.32 (m, 4H), 7.25 (tt, 1H), 3.63 (s, 2H), 2.38 carbonitrile (d, 2H), 2.28 (s, 3H), 2.00-1.90 (m, 9H), 1.90-1.72 (m, 1H), 1.59-1.49 (m, 2H). SC_3259 cis-8-Dimethylamino-3-(2-methyl- SC_3253 2-(bromomethyl)pyridine SC_3105 1H NMR (DMSO-d6): δ 8.94 (s, 2H), 8.52- 457.2 pyrimidin-5-yl)-8-phenyl-1- 8.51 (m, 1H), 7.77-7.74 (m, 1H), 7.45-7.42 (pyridin-2-yl-methyl)-1,3- (d, 1H), 7.38-7.22 (m, 6H), 4.47 (s, 2H), 3.84 diazaspiro[4.5]decan-2-one (s, 2H), 2.66-2.63 (m, 2H), 2.54 (s, 3H), 2.06-2.03 (m, 2H), 1.92(s, 6H), 1.57-1.42 (m, 4H). SC_3260 INT-976 5-bromopyrimidine SC_3103 1H NMR (600 MHz, DMSO) δ 8.98 (s, 2H), 352.2 8.76 (s, 1H), 7.78 (s, 1H), 7.41-7.34 (m, 4H), 7.31-7.24 (m, 1H), 3.65 (s, 2H), 2.49- 2.34 (m, 2H), 1.97 (s, 6H), 1.95-1.76 (m, 4H), 1.50 (t, 2H). SC_3261 cis-8-Dimethylamino-1-[(1- SC_3260 [1-[tert-butyl(dimethyl)silyl]- INT-988 (step 1) 1H NMR (600 MHz, DMSO) δ 9.04 (s, 2H), 436.3 hydroxy-cyclobutyl)-methyl]-8- oxycyclobutyl]methyl 8.80 (s, 1H), 7.37 (d, 4H), 7.27 (p, 1H), 3.83 phenyl-3-pyrimidin-5-yl-1,3- 4-methylbenzenesulfonate (s, 2H), 3.28 (s, 1H), 2.72-2.65 (m, 2H), diazaspiro[4.5]decan-2-one 2.23 (td, 1H), 2.17 (tt, 1H), 2.07 (s, 2H), 2.00 (s, 6H), 1.91 (dt, 2H), 1.72-1.63 (m, 1H), 1.60-1.45 (m, 5H). SC_3262 cis-8-Amino-1-[(1-hydroxy- SC_3255 SC_3099 1H NMR (600 MHz, DMSO) δ 9.29 (s, 2H), 476.2 cyclobutyl)-methyl]-8-phenyl-3-[2- 7.68-7.63 (m, 2H), 7.33 (t, 2H), 7.26-7.18 (trifluoromethyl)-pyrimidin-5-yl]- (m, 1H), 3.97 (s, 2H), 3.45 (s, 2H), 2.43 (td, 1,3-diazaspiro[4.5]decan-2-one 2H), 2.14 (tt, 2H), 1.99 (td, 2H), 1.96-1.90 (m, 2H), 1.71-1.54 (m, 4H), 1.52-1.47 (m, 2H). SC_3263 cis-8-Dimethylamino-3-(3- INT-976 1-bromo-3-fluoro-benzene SC_3103 1H NMR (600 MHz, DMSO) δ 7.58-7.50 368.2 fluorophenyl)-8-phenyl-1,3- (m, 2H), 7.41-7.33 (m, 4H), 7.33-7.23 diazaspiro[4.5]decan-2-one (m, 3H), 6.77-6.71 (m, 1H), 3.58 (s, 2H), 2.48-2.31 (m, 2H), 1.97 (s, 6H), 1.92- 1.80 (m, 4H), 1.47 (t, 2H). SC_3264 cis-8-Dimethylamino-3-(3- INT-976 1-bromo-3- SC_3103 1H NMR (600 MHz, DMSO) δ 8.13 (t, 1H), 428.2 methylsulfonyl-phenyl)-8-phenyl- methylsulfonylbenzene 7.88 (d, 1H), 7.65 (s, 1H), 7.53 (t, 1H), 7.47 1,3-diazaspiro[4.5]decan-2-one (dt, 1H), 7.41-7.35 (m, 4H), 7.28 (qd, 1H), 3.66 (s, 2H), 3.16 (s, 3H), 2.49-2.36 (m, 2H), 1.97 (s, 6H), 1.96-1.74 (m, 4H), 1.53- 1.47 (m, 2H). SC_3265 cis-8-Dimethylamino-3-(4- INT-976 1-bromo-4- SC_3103 1H NMR (600 MHz, DMSO) δ 7.83-7.70 428.2 methylsulfonyl-phenyl)-8-phenyl- methylsulfonylbenzene (m, 5H), 7.41-7.34 (m, 4H), 7.27 (tt, J = 1,3-diazaspiro[4.5]decan-2-one 7.1, 1.9 Hz, 1H), 3.65 (s, 2H), 3.12 (s, 3H), 2.49-2.31 (m, 2H), 1.97 (s, 6H), 1.95- 1.75 (m, 4H), 1.49 (t, J = 8.6 Hz, 2H). SC_3266 cis-8-Dimethylamino-8-phenyl-3- INT-976 3-bromopyridazine SC_3103 1H NMR (600 MHz, DMSO) δ 8.82 (dd, J = 352.2 pyridazin-3-yl-1,3- 4.6, 1.4 Hz, 1H), 8.45 (dd, J = 9.2, 1.4 Hz, diazaspiro[4.5]decan-2-one 1H), 7.95 (br s, 1H), 7.55 (dd, J = 9.2, 4.5 Hz, 1H), 7.42-7.34 (m, 4H), 7.28 (t, J = 6.8 Hz, 1H), 3.83 (s, 2H), 2.47-2.29 (m, 1H), 1.97 (s, 10H), 1.54-1.48 (m, 2H). SC_3267 cis-3-Methoxy-4-(8-methylamino- INT-976 4-bromo-3-methoxy- SC_3103 (for step 1), 1HNMR (DMSO-d6, 400 MHz), δ (ppm) = 391.2 2-oxo-8-phenyl-1,3- benzonitrile (step 1) SC_3099 (for step 2) 7.50-7.50 (m, 2H), 7.42-7.31 (m, 5H), 7.18 diazaspiro[4.5]decan-3-yl)- (bs, 2H), 3.83 (s, 3H), 3.64 (s, 2H), 2.05- benzonitrile 21.99 (m, 2H), 1.85 (bs, 5H), 1.70 (bs, 2H), 1.53-1.50 (m, 2H). SC_3268 cis-8-Dimethylamino-3-(2- INT-976 1-bromo-2-luorobenzene SC_3103 1H NMR (600 MHz, DMSO) δ 7.46 (td, J = 368.2 fluorophenyl)-8-phenyl-1,3- 8.0, 1.6 Hz, 1H), 7.40-7.32 (m, 5H), 7.26 diazaspiro[4.5]decan-2-one (td, J = 6.7, 3.3 Hz, 1H), 7.24-7.12 (m, 3H), 3.53 (s, 2H), 2.37-2.33 (m, 2H), 1.96 (s, 6H), 1.95-1.74 (m, 4H), 1.49 (t, J = 9.3 Hz, 2H). SC_3269 cis-8-Dimethylamino-8-phenyl-3- INT-976 5-bromo-2-phenyl-pyrimidine SC_3103 1H NMR (600 MHz, DMSO) δ 9.07 (s, 2H), 428.3 (2-phenyl-pyrimidin-5-yl)-1,3- 8.34-8.28 (m, 2H), 7.82 (s, 1H), 7.52- diazaspiro[4.5]decan-2-one 7.42 (m, 4H), 7.39 (s, 1H), 7.38 (s, 3H), 7.28 (t, J = 4.8 Hz, 1H), 3.70 (s, 2H), 2.43-2.39 (m, 2H), 2.06-1.72 (m, 10H), 1.52 (d, J = 10.8 Hz, 2H). SC_3270 cis-8-Methylamino-1-(oxetan-3-yl- SC_3245 oxetan-3-ylmethyl 4- SC_3099 (for step1), 1H NMR (DMSO-d6): δ 9.24 (s, 2H), 7.49 476.2 methyl)-8-phenyl-3-[2- methylbenzenesulfonate (step 2) SC_3105 (for step 2) (d, 2H), 7.34 (t, 2H), 7.21 (t, 1H), 4.66-4.62 (trifluoromethyl)-pyrimidin-5-yl]- (m, 2H), 4.44 (t, 2H), 3.87 (s, 2H), 3.55 (d, 1,3-diazaspiro[4.5]decan-2-one 2H), 3.28-3.23 (m, 1H), 2.36 (m, 1H), 2.20- 2.14 (m, 2H), 1.95-1.91 (m, 5H), 1.84-1.77 (m, 2H), 1.43-1.40 (m, 2H). SC_3271 cis-1-(Cyclopropyl-methyl)-8- SC_3245 (bromomethyl)-cyclopropane SC_3099 (for step1), 1H NMR (DMSO-d6): δ 9.26 (s, 2H), 7.50 460.1 methylamino-8-phenyl-3-[2- SC_3105 (for step 2) (d, 2H), 7.35 (t, 2H), 7.22 (t, 1H), 3.89 (s, (trifluoromethyl)-pyrimidin-5-yl]- 2H), 3.13 (d, 2H), 2.29-2.23 (m, 3H), 1.92- 1,3-diazaspiro[4.5]decan-2-one 1.82 (m, 7H), 1.47-1.44 (m, 2H), 1.08-1.05 (m, 1H), 0.52-0.48 (m, 2H), 0.36-0.36-0.32 (m, 2H). SC_3272 cis-4-(8-Dimethylamino-2-oxo-8- INT-976 4-bromobenzonitrile SC_3103 1H NMR (600 MHz, DMSO) δ 7.82-7.71 375.2 phenyl-1,3-diazaspiro[4.5]decan-3- (m, 3H), 7.72-7.67 (m, 2H), 7.41-7.33 yl)-benzonitrile (m, 4H), 7.30-7.23 (m, 1H), 3.63 (s, 2H), 2.45-2.39 (m, 2H), 1.97 (s, 6H), 1.95- 1.72 (m, 4H), 1.51-1.44 (m, 2H). SC_3273 cis-8-Dimethylamino-3-(4- INT-976 1-bromo-4-fluoro-benzene SC_3103 368.2 fluorophenyl)-8-phenyl-1,3- diazaspiro[4.5]decan-2-one SC_3274 cis-2-(8-Dimethylamino-2-oxo-8- INT-976 2-bromobenzonitrile SC_3103 1H NMR (600 MHz, DMSO) δ 7.77 (dd, J = 375.2 phenyl-1,3-diazaspiro[4.5]decan-3- 7.5, 1.6 Hz, 1H), 7.66 (ddd, J = 8.3, 7.5, 1.6 yl)-benzonitrile Hz, 1H), 7.60 (s, 1H), 7.48 (dd, J = 8.3, 1.1 Hz, 1H), 7.39-7.34 (m, 4H), 7.32 (td, J = 7.5, 1.1 Hz, 1H), 7.26 (tt, J = 7.5, 1.6 Hz, 1H), 3.68 (s, 2H), 2.46-2.30 (m, 2H), 2.01- 1.75 (m, 10H), 1.59-1.50 (m, 2H). SC_3276 cis-1-[(1-Hydroxy-cyclobutyl)- SC_3256 SC_3099 1H NMR (600 MHz, DMSO) δ 8.94 (s, 2H), 436.3 methyl]-8-methylamino-3-(2- 7.53-7.47 (m, 2H), 7.39-7.30 (m, 2H), methyl-pyrimidin-5-yl)-8-phenyl- 7.24-7.17 (m, 1H), 3.83 (s, 2H), 3.54- 1,3-diazaspiro[4.5]decan-2-one 3.36 (m, 2H), 2.56 (s, 3H), 2.28 (td, 2H), 2.18-2.09 (m, 2H), 1.97-1.86 (m, 7H), 1.81 (td, 2H), 1.71-1.61 (m, 1H), 1.59- 1.47 (m, 1H), 1.49-1.42 (m, 2H). SC_3277 cis-8-Dimethylamino-3-[2- INT-976 4-[(5-bromopyrimidin-2- SC_3103 1H NMR (600 MHz, DMSO) δ 8.93 (s, 2H), (morpholin-4-yl-methyl)- yl)methyl]morpholine 7.87-7.65 (m, 1H), 7.42-7.34 (m, 4H), pyrimidin-5-yl]-8-phenyl-1,3- 7.28 (dq, 1H), 3.66-3.62 (m, 2H), 3.61 (s, diazaspiro[4.5]decan-2-one 2H), 3.54 (t, 4H), 2.43 (t, 4H), 1.98 (s, 6H), 1.96-1.74 (m, 4H), 1.52-1.46 (m, 2H). SC_3278 cis-8-Dimethylamino-3-[2-(methyl- INT-989 N-methyltetrahydro- SC_3120 1H NMR (DMSO-d6): δ 8.50 (s, 2H), 7.39- 465.2 tetrahydro-pyran-4-yl-amino)- 2H-pyran-4-amine 7.35 (m, 5H), 7.27-7.24 (m, 1H), 4.74-4.67 pyrimidin-5-yl]-8-phenyl-1,3- (m, 1H), 3.94-3.90 (m, 2H), 3.50 (s, 2H), diazaspiro[4.5]decan-2-one 3.39 (t, 2H), 2.93 (s, 3H), 2.35 (m, 2H), 1.99-1.71 (m, 12H), 1.50-1.44 (m, 4H). SC_3279 cis-5-[8-Dimethylamino-1-[(1- INT-990 (1-(tert- SC_3105 (step 1), 1H NMR (DMSO-d6): δ 9.12 (s, 2H), 8.63 669.4 hydroxy-cyclobutyl)-methyl]-2- butyldimethylsilyloxy)cyclobutyl)methyl SC_3133 (step 2) (t, 1H), 7.36-7.33 (m, 4H), 7.26-7.23 (m, oxo-8-phenyl-1,3- 4-methylbenzenesulfonate (step 1), 1H), 5.25 (s, 1H), 3.85 (s, 2H), 3.52-3.34 (m, diazaspiro[4.5]decan-3-yl]-N-[2-[2- 2,5,8,11-tetraoxatridecan-13- 16H), 3.35 (m, 2H), 3.19 (s, 3H), 2.69-2.66 [2-(2-methoxy-ethoxy)-ethoxy]- amine (step 2) (m, 2H), 2.25-2.13 (m, 4H), 1.97 (s, 6H), ethoxy]-ethyl]-pyrimidine-2- 1.92-1.87 (m, 2H), 1.57-1.44 (m, 6H). carboxylic acid amide SC_3280 cis-1-(Cyclopropyl-methyl)-3-(2- INT-976 1-bromo-2-fluoro-4- SC_3103 (for step 1), 1H NMR (DMS0-d6): δ 7.86 (t, 1H), 7.81- 486.2 fluoro-4-methylsulfonyl-phenyl)-8- (methylsulfonyl)benzene (step 1), SC_3105 (step 2), 7.77 (m, 1H), 7.73-7.70 (m, 1H), 7.45 (d, methylamino-8-phenyl-1,3- (Bromomethyl)cyclopropane (step 2) SC_3099 (step 3) 2H), 7.31 (t, 2H), 7.19 (t, 1H), 3.85 (s, 2H), diazaspiro[4.5]decan-2-one 3.24 (s, 3H), 3.09 (d, 2H), 2.29-2.22 (m, 3H), 1.93-1.90 (m, 5H), 1.74-1.68 (m, 2H), 1.49- 1.46 (m, 2H), 1.04 (m, 1H), 0.51-0.46 (m, 2H), 0.34-0.30 (m, 2H). SC_3281 cis-2-[[5-(8-Dimethylamino-2-oxo- INT-989 2-(methylamino)acetamide SC_3120 1H NMR (DMSO-d6): δ 8.48 (s, 2H), 7.39- 438.2 8-phenyl-1,3-diazaspiro[4.5]decan- hydrochloride 7.35 (m, 5H), 7.27-7.25 (m, 2H), 6.89 (s, 3-yl)-pyrimidin-2-yl]-methyl- 1H), 4.08 (s, 2H), 3.51 (s, 2H), 3.07 (s, 3H), amino]-acetamide 2.36-2.33 (m, 2H), 1.94-1.86 (m, 10H), 1.45 (m, 2H). SC_3282 cis-2-[[5-(8-Dimethylamino-2-oxo- INT-976 tert-butyl (5-bromopyrimidin-2- SC_3103 (for step 1), 1H NMR (DMS0-d6): δ 8.45 (s, 2H), 7.39- 424.2 8-phenyl-1,3-diazaspiro[4.5]decan- yl)(cyanomethyl)carbamate (step 1) SC_3100 step 3 (for step 2) 7.33 (m, 5H), 7.27-7.22 (m, 2H), 6.92 (s, 3-yl)-pyrimidin-2-yl]amino]- 1H), 6.86 (t, 1H), 3.74 (d, 2H), 3.51 (s, 2H), acetamide 2.46-2.28 (m, 2H), 1.95-1.86 (m, 10H), 1.45 (m, 2H). SC_3283 cis-1-(Cyclopropyl-methyl)-8- SC_3284 SC_3099 1H NMR (DMS0-d6): δ 8.61 (s, 1H), 7.82 473.3 methylamino-3-[4-methyl-6- (s, 1H), 7.46-7.44 (m, 2H), 7.30 (t, 2H), 7.18 (trifluoromethyl)-pyridin-3-yl]-8- (t, 1H), 3.80 (s, 2H), 3.08 (d, 2H), 2.33-2.25 phenyl-1,3-diazaspiro[4.5]decan-2- (m, 6H), 1.92-1.89 (m, 5H), 1.72 (t, 2H), one 1.56-1.53 (m, 2H), 1.04 (m, 1H), 0.51-0.46 (m, 2H), 0.33-0.30 (m, 2H). SC_3284 cis-1-(Cyclopropyl-methyl)-8- INT-984 5-bromo-4-methyl-2- SC_3103 1H NMR(DMSO-d6): δ 8.59 (s, 1H), 7.82 487.3 dimethylamino-3-[4-methyl-6- (trifluoromethyl)pyridine (s, 1H), 7.35-7.34 (m, 4H), 7.27-7.23 (m, (trifluoromethyl)-pyridin-3-yl]-8- 1H), 3.75 (s, 2H), 3.06 (d, 2H), 2.71-2.68 (m, phenyl-1,3-diazaspiro[4.5]decan-2- 2H), 2.33-2.24 (m, 5H), 2.00 (m, 6H), 1.59- one 1.56 (m, 2H), 1.46 (t, 2H), 1.02-0.99 (m, 1H), 0.53-0.48 (m, 2H), 0.33-0.30 (m, 2H). SC_3285 cis-N-[5-(8-Dimethylamino-2-oxo- SC_3239 thiophene-2-carbonyl chloride SC_3240 1H NMR (600 MHz, DMSO) δ 8.90 (s, 2H), 477.2 8-phenyl-1,3-diazaspiro[4.5]decan- 8.08-8.04 (m, 1H), 7.84 (dd, 1H), 7.71 (s, 3-yl)-pyrimidin-2-yl]-thiophene-2- 1H), 7.38 (d, 5H), 7.27 (td, 1H), 7.19 (dd, carboxylic acid amide 1H), 3.66 (s, 2H), 2.48-2.34 (m, 2H), 1.99- 1.75 (m, 10H), 1.54-1.48 (m, 2H). SC_3286 cis-N-[5-(8-Dimethylamino-2-oxo- SC_3239 benzoyl chloride SC_3240 1H NMR (600 MHz, DMSO) δ 10.84 (s, 471.3 8-phenyl-1,3-diazaspiro[4.5]decan- 1H), 8.91 (s, 2H), 7.98-7.93 (m, 2H), 7.62- 3-yl)-pyrimidin-2-yl]-benzamide 7.55 (m, 1H), 7.50 (t, 2H), 7.39 (d, 4H), 7.28 (dt, 1H), 3.67 (s, 2H), 2.48-2.32 (m, 2H), 2.05-1.76 (m, 10H), 1.55-1.49 (m, 2H). SC_3287 cis-8-Dimethylamino-8-phenyl-3- INT-976 2-bromo-5-phenylthiophene SC_3103 1H NMR (DMSO-d6): δ 7.80-7.70 (br s, 432.2 (5-phenyl-thiophen-2-yl)-1,3- 1H), 7.52 (d, 2H), 7.38-7.28 (m, 7H), 7.20- diazaspiro[4.5]decan-2-one 7.17 (m, 2H), 6.27 (d, 1H), 3.61 (s, 2H), 2.49 (m, 2H), 1.95-1.91 (m, 10H), 1.48 (m, 2H). SC_3288 cis-1-(Cyclopropyl-methyl)-8- INT-984 1-bromo-2- SC_3103 1H NMR (CDCl3): δ 7.49 (d, 1H), 7.41-7.22 496.3 dimethylamino-3-[2- (methylsulfonylmethyl)benzene (m, 8H), 4.45 (s, 2H), 3.64 (s, 2H), 3.15 (d, (methylsulfonyl-methyl)-phenyl]-8- 2H), 2.79 (s, 3H), 2.71-2.67 (m, 2H), 2.37 (t, phenyl-1,3-diazaspiro[4.5]decan-2- 2H), 2.06 (s, 6H), 1.67-1.64 (m, 2H), 1.55- one 1.44 (m, 2H), 1.10-1.06 (m, 1H), 0.57-0.52 (m, 2H), 0.39-0.35 (m, 2H). SC_3289 cis-1-(Cyclopropyl-methyl)-8- SC_3288 SC_3099 1H NMR (DMSO-d6): δ 7.49-7.37 (m, 5H), 482.3 methylamino-3-[2-(methylsulfonyl- 7.32-7.30 (m, 3H), 7.19-7.15 (m, 1H), 4.49 methyl)-phenyl]-8-phenyl-1,3- (s, 2H), 3.71 (s, 2H), 3.05 (d, 2H), 2.87 (s, diazaspiro[4.5]decan-2-one 3H), 2.26-2.20 (m, 3H), 1.91-1.87 (m, 5H), 1.71-1.56 (m, 4H), 1.03-1.01 (m, 1H), 0.49- 0.45 (m, 2H), 0.31-0.28 (m, 2H). SC_3290 cis-8-Dimethylamino-8-(3- INT-1024 1-bromo-2- SC_3103 1H NMR (600 MHz, DMSO) δ 7.46 (dd, 460.3 fluorophenyl)-3-[2- (methylsulfonylmethyl)benzene 1H), 7.39 (td, 2H), 7.33 (dd, 1H), 7.31-7.21 (methylsulfonyl-methyl)-phenyl]- (m, 1H), 7.18 (d, 1H), 7.15 (dd, 1H), 7.08 1,3-diazaspiro[4.5]decan-2-one (td, 1H), 4.50 (s, 2H), 3.56 (s, 2H), 2.88 (s, 3H), 2.42-2.24 (m, 2H), 1.99-1.89 (m, 8H), 1.88-1.75 (m, 2H), 1.60-1.48 (m, 2H). SC_3291 cis-8-Dimethylamino-8-(4- INT-1025 1-bromo-2- SC_3103 1H NMR (600 MHz, DMSO) δ 7.46 (dd, 460.3 fluorophenyl)-3-[2- (methylsulfonylmethyl)benzene 1H), 7.43-7.34 (m, 3H), 7.33 (dd, 1H), 7.28 (methylsulfonyl-methyl)-phenyl]- (td, 2H), 7.16 (t, 2H), 4.49 (s, 2H), 3.55 (s, 1,3-diazaspiro[4.5]decan-2-one 2H), 2.88 (s, 3H), 2.35-2.32 (m, 2H), 1.95 (s, 6H), 1.94-1.88 (m, 2H), 1.88-1.65 (m, 2H), 1.59-1.47 (m, 2H). SC_3294 cis-8-Dimethylamino-8-(3- INT-1024 4-(5-bromo-4-methyl- SC_3103 1H NMR (600 MHz, DMSO) δ 8.13 (s, 1H), 469.3 fluorophenyl)-3-(4-methyl-2- pyrimidin-2-yl)morpholine 7.40 (td, 1H), 7.22-7.11 (m, 4H), 7.08 (td, morpholin-4-yl-pyrimidin-5-yl)- 1H), 3.69-3.60 (m, 8H), 2.34-2.31 (m, 1,3-diazaspiro[4.5]decan-2-one 2H), 2.20 (s, 3H), 1.96 (s, 6H), 1.96-1.70 (m, 4H), 1.56-1.43 (m, 2H). SC_3295 cis-3-[6-(4-Acetyl-piperazin-1-yl)- INT-976 1-[4-(5-bromo-4-methyl-pyridin-2-yl)- SC_3103 1HNMR (DMSO-d6, 400 MHz at 100 0 C.), δ 491.3 4-methyl-pyridin-3-yl]-8- piperazin-1-yl]-ethanone (ppm) = 7.88 (s, 1H), 7.35-7.22 (m, 5H), dimethylamino-8-phenyl-1,3- 6.73 (s, 1H), 6.64 (s, 1H), 3.53-3.50 (m, 8H), diazaspiro[4.5]decan-2-one 3.38 (s, 2H), 2.33-2.30 (m, 2H), 2.14 (s, 3H), 2.03-1.88 (m, 13H), 1.56-1.51 (m, 2H). SC_3296 cis-3-[2-(4-Acetyl-piperazin-1-yl)- INT-976 1-[4-(5-bromo-4-methyl-pyrimidin-2- SC_3103 1H-NMR (DMSO-d6, 400 MHz at 100 0 C.), 492.3 4-methyl-pyrimidin-5-yl]-8- yl)-piperazin-1-yl]-ethanone δ (ppm) = 8.11 (s, 1H), 7.35-7.24 (m, 5H), dimethylamino-8-phenyl-1,3- 6.88 (s, 1H), 3.73 (bs, 4H), 3.52 (bs, 4H), diazaspiro[4.5]decan-2-one 3.38 (s, 2H), 2.33 (bs, 2H), 2.22 (s, 3H), 2.03-1.87 (m, 13H), 1.56-1.53 (m, 2H). SC_3297 cis-8-Dimethylamino-3-(4-methyl- INT-976 5-bromo-2-chloro-4- SC_3103 (for step 1), 1H-NMR (DMSO-d6, 400 MHz at 100 0 C.), 442.3 6-pyridin-4-yl-pyridin-3-yl)-8- methyl-pyridine (step 1), SC_3129 (for step 2) δ (ppm) = 8.65 (d, 2H, J = 5.92 Hz), phenyl-1,3-diazaspiro[4.5]decan-2- 4-pyridinylboronic acid (step 2) 8.50 (s, 1H), 7.96 (d, 2H, J = 5.96 Hz), 7.91 one (s, 1H), 7.36-7.23 (m, 5H), 7.07 (s, 1H), 3.57 (s, 2H), 2.38-2.33 (m, 5H), 2.04 (s, 6H), 2.00-1.88 (m, 4H), 1.61-1.57 (m, 2H). SC_3298 cis-3-[2-(4-Acetyl-piperazin-1-yl)- INT-976 1-[4-(5-bromo-4-trifluoromethyl- SC_3103 1H-NMR (DMSO-d6, 400 MHz at 100 0 C.), 546.3 4-(trifluoromethyl)-pyrimidin-5- pyrimidin-2-yl)-piperazin-1-yl]- δ (ppm) = 8.52 (s, 1H), 7.35-7.22 (m, 5H), yl]-8-dimethylamino-8-phenyl-1,3- ethanone 7.07 (s, 1H), 3.79-3.78 (t, 4H, 5.08 Hz), 3.57 diazaspiro[4.5]decan-2-one (t, 4H, 5.26 Hz), 3.39 (s, 2H), 2.36-2.32 (m, 2H), 2.04-1.85 (m, 13H), 1.54-1.50 (m, 2H). SC_3299 cis-8-Dimethylamino-3-[2-(3-oxo- INT-976 4-(5-bromo-4-trifluoromethyl- SC_3103 1HNMR (DMSO-d6, 400 MHz), δ (ppm) = 518.2 piperazin-1-yl)-4-(trifluoromethyl)- pyrimidin-2-yl)-piperazin-2-one 8.55 (s, 1H), 7.77 (bs, 1H), 7.35-7.23 (m, pyrimidin-5-yl]-8-phenyl-1,3- 5H), 7.09 (s, 1H), 4.20 (s, 2H), 3.92 (t, 2H, diazaspiro[4.5]decan-2-one J = 5.04 Hz), 3.39 (s, 2H), 3.33 (bs, 2H), 2.36- 2.33 (m, 2H), 2.03-1.85 (m, 10H), 1.54-1.39 (m, 2H). SC_3300 cis-8-Dimethylamino-3- INT-976 4-bromo-isoquinoline SC_3103 1HNMR (DMSO-d6, 400 MHz at 100 0 C.), δ 401.2 isoquinolin-4-yl-8-phenyl-1,3- (ppm) = 9.16 (s, 1H), 8.41 (s, 1H), 8.13 (d, diazaspiro[4.5]decan-2-one 1H, J = 8.12 Hz), 7.91 (d, 1H, J = 8.64 Hz), 7.71 (t, 1H, J = 7.58 Hz), 7.67 (t, 1H, J = 7.46 Hz), 7.36-7.23 (m, 5H), 7.14 (s, 1H), 3.67 (s, 2H), 2.41-2.36 (m, 2H), 2.10-1.89 (m, 10H), 1.68-1.64 (m, 2H). SC_3301 cis-8-Dimethylamino-3- INT-976 5-bromo-isoquinoline SC_3103 1HNMR (DMSO-d6, 400 MHz at 100 0 C.), δ 401.2 isoquinolin-5-yl-8-phenyl-1,3- (ppm) = 9.29 (s, 1H), 8.48 (d, 1H, J = 5.92 diazaspiro[4.5]decan-2-one Hz) 7.98-7.96 (m, 1H), 7.70-7.64 (m, 3H), 7.36-7.23 (m, 5H), 7.13 (s, 1H), 3.65 (s, 2H), 2.41-2.36 (m, 2H), 2.10-1.90 (m, 10H), 1.68- 1.63 (m, 2H). SC_3302 cis-8-Dimethylamino-8-phenyl-3- INT-976 4-bromo-1H-pyrrolo[2,3-b]pyridine SC_3103 1H NMR (600 MHz, DMSO) δ 11.42 (s, 390.2 (1H-pyrrolo[2,3-b]pyridin-4-yl)- 1H), 7.99 (d, 1H), 7.66 (br s, 1H), 7.43- 1,3-diazaspiro[4.5]decan-2-one 7.33 (m, 5H), 7.27 (t, 1H), 7.22 (t, 1H), 6.65- 6.60 (m, 1H), 3.91 (s, 2H), 2.45-2.27 (m, 2H), 1.98-1.82 (m, 10H), 1.56-1.49 (m, 2H). SC_3303 cis-8-Dimethylamino-8-phenyl-3- INT-976 4-bromo-2-(pyridin-4-yl)thiazole SC_3103 1H NMR (DMSO-d6): δ 8.62 (d, 2H), 7.82 434.1 (2-pyridin-4-yl-thiazol-4-yl)-1,3- (d, 2H), 7.61 (broad s, 1H), 7.54 (s, 1H), diazaspiro[4.5]decan-2-one 7.40-7.37 (m, 4H), 7.29-7.27 (m, 1H), 3.84 (s, 2H), 2.49 (m, 2H), 1.96-1.79 (m, 10H), 1.51 (m, 2H). SC_3304 cis-8-[Methyl-(tetrahydro-furan-3- INT-1026 4-(5-bromopyrimidin-2-yl)morpholine step 2 of SC_3097 (for synthesis), 1H NMR (DMSO-d6): δ 8.56 (s, 2H), 7.65 507.3 yl-methyl)-amino]-3-(2-morpholin- SC_3292 and SC_3293 (broad s, 1H), 7.36-7.23 (m, 5H), 3.66-3.55 4-yl-pyrimidin-5-yl)-8-phenyl-1,3- (for separation of enantiomers) (m, 10H), 3.49 (s, 2H), 3.38 (m, 1H), 2.32- diazaspiro[4.5]decan-2-one 2.26 (m, 3H), 2.11-1.94 (m, 6H), 1.86-1.82 (enantiomer 1) (m, 3H), 1.50-1.41(m, 3H). SC_3305 cis-8-[Methyl-(tetrahydro-furan-3- INT-1026 4-(5-bromopyrimidin-2-yl)morpholine step 2 of SC_3097 (for synthesis), 1H NMR (DMSO-d6): δ 8.56 (s, 2H), 7.66 507.2 yl-methyl)-amino]-3-(2-morpholin- SC_3292 and SC_3293 (broad s, 1H), 7.35-7.24 (m, 5H), 3.63-3.49 4-yl-pyrimidin-5-yl)-8-phenyl-1,3- (for separation of enantiomers) (m, 12H), 3.31 (m, 1H), 2.27 (m, 3H), 2.11- diazaspiro[4.5]decan-2-one 1.84 (m, 10H), 1.42 (m, 3H). (enantiomer 2) SC_3306 cis-3-[2-(Azetidin-1-yl)-pyrimidin- INT-976 2-azetidin-1-yl-5-bromo-pyrimidine step 2 of SC_3242 1HNMR (DMSO-d6, 400 MHz at 100 0 C.), δ 407.2 5-yl]-8-dimethylamino-8-phenyl- (ppm) = 8.48 (s, 2H), 7.36-7.26 (m, 5H), 1,3-diazaspiro[4.5]decan-2-one 7.07 (s, 1H), 3.99 (t, 4H, J = 7.18 Hz), 3.50 (s, 2H), 2.35-2.26 (m, 4H), 2.03 (s, 6H), 1.95-1.91 (m, 2H), 1.52-1.50 (m, 2H). SC_3307 cis-3-[2-(3,3-Difluoro-azetidin-1- INT-976 5-bromo-2-(3,3-difluoro-azetidin-1- step 2 of SC_3242 1HNMR (DMSO-d6, 400 MHz at 100 0 C.), δ 443.2 yl)-pyrimidin-5-yl]-8- yl)-pyrimidine (ppm) = 8.62 (s, 2H), 7.37-7.25 (m, 5H), dimethylamino-8-phenyl-1,3- 7.20 (s, 1H), 4.38 (t, 4H, J = 12.40 Hz), 3.55 diazaspiro[4.5]decan-2-one (s, 2H), 2.36-233 (m, 2H), 2.03 (s, 6H) 1.97- 1.89 (m, 4H), 1.53-1.51 (m, 2H). SC_3308 cis-8-Dimethylamino-3-[6- INT-976 4-(5-bromo-3-trifluoromethyl- SC_3103 1HNMR (DMSO-d6, 400 MHz at 100 0 C.), δ 504.3 morpholin-4-yl-5-(trifluoromethyl)- pyridin-2-yl)-morpholine (ppm) = 8.63 (s, 1H), 8.38 (s, 1H), 7.37-7.25 pyridin-3-yl]-8-phenyl-1,3- (m, 6H), 3.71 (bs, 4H), 3.65 (s, 2H), 3.03 diazaspiro[4.5]decan-2-one (bs, 4H), 2.37-2.32 (m, 2H), 2.03 (s, 6H), 1.98-1.88 (m, 4H), 1.55-1.52 (m, 2H). SC_3309 cis-8-Methylamino-3-[6- SC_3308 SC_3099 1HNMR (DMSO-d6, 400 MHz at 100 0 C.), δ 490.4 morpholin-4-yl-5-(trifluoromethyl)- (ppm) = 8.68 (s, 1H), 8.42 (s, 1H), 7.48 (d, pyridin-3-yl]-8-phenyl-1,3- 2H, J = 8.12 Hz), 7.33 (t, 2H, J = 7.62 Hz), diazaspiro[4.5]decan-2-one 7.20 (t, 1H, J = 7.38 Hz), 7.14 (s, 1H), 3.75- 3.71 (m, 6H), 3.03 (t, 4H, J = 8.88 Hz), 2.08- 2.02 (m, 2H), 1.95-1.79 (m, 8H), 1.58-1.55 (m, 2H). SC_3310 cis-8-Dimethylamino-8-phenyl-3- INT-976 2-bromo-5-(trifluoromethoxy)- SC_3103 1H NMR (600 MHz, DMSO) δ 8.32-8.26 435.2 [5-(trifluoromethyloxy)-pyridin-2- pyridine (m, 2H), 7.86-7.82 (m, 1H), 7.79 (dd, 1H), yl]-1,3-diazaspiro[4.5]decan-2-one 7.41-7.33 (m, 4H), 7.27 (t, 1H), 3.71 (s, 2H), 2.46-2.33 (m, 2H), 1.96 (s, 6H), 1.94- 1.72 (m, 4H), 1.47 (t, 2H). SC_3311 cis-8-Dimethylamino-3-(5- INT-976 2-bromo-5- SC_3103 1H NMR (600 MHz, DMSO) δ 8.66 (dd, 429.2 methylsulfonyl-pyridin-2-yl)-8- methylsulfonylpyridine 1H), 8.39 (dd, 1H), 8.14 (dd, 1H), 8.06 (s, phenyl-1,3-diazaspiro[4.5]decan-2- 1H), 7.42-7.33 (m, 4H), 7.28 (t, 1H), 3.77 one (s, 2H), 3.21 (s, 3H), 2.46-2.32 (m, 2H), 2.03-1.68 (m, 10H), 1.52-1.46 (m, 2H). SC_3312 cis-6-(8-Dimethylamino-2-oxo-8- INT-976 6-bromopyridine-3- SC_3103 1H NMR (600 MHz, DMSO) δ 8.66 (d, 1H), 376.2 phenyl-1,3-diazaspiro[4.5]decan-3- carbonitrile 8.34 (d, 1H), 8.08 (dd, 1H), 7.41-7.33 (m, yl)-nicotinonitrile 4H), 7.28 (t, 1H), 3.74 (s, 2H), 2.46-2.30 (m, 2H), 1.96 (s, 6H), 1.94-1.73 (m, 4H), 1.51-1.44 (m, 2H). SC_3314 cis-8-Dimethylamino-3-[4-methyl- INT-976 4-(5-bromo-4-methyl-pyrimidin- SC_3103 1HNMR (DMSO-d6, 400 MHz at 100° C.), δ 464.2 2-(3-oxo-piperazin-1-yl)-pyrimidin- 2-yl)-piperazin-2-one (ppm) = 8.14 (s, 1H), 7.65 (bs, 1H), 7.34- 5-yl]-8-phenyl-1,3- 7.23 (m, 5H), 6.89 (s, 1H), 4.16 (s, 2H), 3.88 diazaspiro[4.5]decan-2-one (bs, 2H), 3.39 (s, 2H), 3.29 (bs, 2H), 2.33 (bs, 2H), 2.24 (s, 3H), 2.03-1.87 (m, 10H), 1.53 (bs, 2H). SC_3315 cis-5-(8-Dimethylamino-2-oxo-8- SC_3312 SC_3016 1H NMR (600 MHz, DMSO) δ 8.80 (d, 1H), 394.2 phenyl-1,3-diazaspiro[4.5]decan-3- 8.10 (dd, 1H), 7.95-7.89 (m, 2H), 7.79 (s, yl)-pyridine-2-carboxylic acid 1H), 7.42-7.35 (m, 5H), 7.28 (s, 1H), 3.67 amide (s, 2H), 2.48-2.28 (m, 2H), 1.95 (d, 10H), 1.53-1.46 (m, 2H). SC_3316 cis-3-[4-(Azetidin-1-yl)-2-methyl- INT-976 4-azetidin-1-yl-5- step 2 of SC_3242 1HNMR (DMSO-d6, 400 MHz at 100 0 C.), δ 421.2 pyrimidin-5-yl]-8-dimethylamino- bromo-2-methyl-pyrimidine (ppm) = 7.85 (s, 1H), 7.34-7.23 (m, 5H), 8-phenyl-1,3-diazaspiro[4.5]decan- 6.93 (s, 1H), 4.11 (t, 4H, J = 7.40 Hz), 3.33 2-one (s, 2H), 2.33-2.30 (m, 7H), 2.02 (s, 6H), 1.96-1.87 (m, 4H), 1.53-1.48 (m, 2H). SC_3317 cis-2-(8-Dimethylamino-2-oxo-8- INT-976 2-bromobenzonitrile SC_3103 (step 1), 1H NMR (600 MHz, DMSO) δ 7.50 (s, 1H), 393.2 phenyl-1,3-diazaspiro[4.5]decan-3- SC_3016 (step 2) 7.42 (dd, 1H), 7.42-7.32 (m, 5H), 7.31 (d, yl)-benzamide 1H), 7.26 (t, 1H), 7.23-7.13 (m, 3H), 3.53 (s, 2H), 2.41-2.27 (m, 2H), 1.96 (s, 6H), 1.90 (t, 2H), 1.86-1.68 (m, 2H), 1.52-1.48 (m, 2H). SC_3318 cis-8-Dimethylamino-3-[2- INT-997 1-bromo-2- SC_3103 1H NMR (600 MHz, DMSO) δ 7.47 (dd, 448.2 (methylsulfonyl-methyl)-phenyl]-8- (methylsulfonylmethyl)-benzene 1H), 7.43-7.36 (m, 2H), 7.34 (dd, 1H), 7.29 thiophen-2-yl-1,3- (ddd, 1H), 7.19 (s, 1H), 7.05 (ddd, 1H), 6.94 diazaspiro[4.5]decan-2-one (d, 1H), 4.50 (s, 2H), 3.61 (s, 2H), 2.89 (s, 3H), 2.35-2.21 (m, 2H), 2.04 (s, 6H), 1.98- 1.90 (m, 2H), 1.86-1.70 (m, 2H), 1.66- 1.59 (m, 2H). SC_3320 cis-8-Dimethylamino-3-(4-methyl- INT-997 4-(5-bromo-4-methyl- SC_3319 1H NMR (600 MHz, DMSO) δ 8.15 (d, 1H), 457.2 2-morpholin-4-yl-pyrimidin-5-yl)- pyrimidin-2-yl)morpholine 7.41 (dt, 1H), 7.13 (s, 1H), 7.05 (ddd, 1H), 8-thiophen-2-yl-1,3- 6.94 (dd, 1H), 3.71-3.60 (m, 8H), 3.44 (s, diazaspiro[4.5]decan-2-one 2H), 2.32-2.24 (m, 2H), 2.21 (s, 3H), 2.04 (s, 6H), 1.98-1.88 (m, 2H), 1.87-1.75 (m, 2H), 1.62-1.54 (m, 2H). SC_3321 cis-8-Dimethylamino-3-(6- INT-976 5-bromo-2- SC_3103 1H NMR (600 MHz, DMSO) δ 8.89 (d, J = 429.2 methylsulfonyl-pyridin-3-yl)-8- methylsulfonylpyridine 2.6 Hz, 1H), 8.28 (dd, J = 8.9, 2.6 Hz, 1H), phenyl-1,3-diazaspiro[4.5]decan-2- 7.93 (d, 1H), 7.42-7.34 (m, 4H), 7.31- one 7.25 (m, 1H), 3.71 (s, 2H), 3.18 (s, 3H), 2.48- 2.33 (m, 2H), 2.04-1.76 (m, 10H), 1.54- 1.48 (m, 2H). SC_3322 cis-8-Dimethylamino-8-phenyl-3- INT-976 tert-butyl 5-bromopyrrolo[2,3- SC_3103 (for step 1), 1H NMR (600 MHz, DMSO) δ 11.45 (s, 390.2 (1H-pyrrolo[2,3-b]pyridin-5-yl)- b]pyridine-1-carboxylate (step 1) SC_3173 (for step 2) 1H), 8.38 (s, 1H), 8.00 (d, 1H), 7.85-7.81 1,3-diazaspiro[4.5]decan-2-one (m, 1H), 7.70-7.66 (m, 2H), 7.57-7.53 (m, 3H), 7.41 (t, 1H), 6.35 (dd, 1H), 3.54 (s, 2H), 2.75-2.41 (m, 8H, overlapps with solvent residual peak), 2.30-2.26 (m, 2H), 1.89 (d, 2H), 1.41-1.37 (m, 2H). SC_3323 cis-N-[5-(8-Dimethylamino-2-oxo- SC_3239 acetyl chloride SC_3240 1H NMR (600 MHz, DMSO) δ 10.36 (s, 409.2 8-phenyl-1,3-diazaspiro[4.5]decan- 1H), 8.82 (s, 2H), 8.40 (s, rotamer), 7.67 (s, 3-yl)-pyrimidin-2-yl]-acetamide 1H), 7.44-7.31 (m, 4H), 7.27 (td, 1H), 3.62 (enantiomer 1) (s, 2H), 2.46-2.30 (m, 2H), 2.11 (s, 3H), 2.08 (s, rotamer), 1.96 (s, 6H), 1.97 (s, rotamer), 1.95-1.75 (m, 4H), 1.52-1.47 (m, 2H). SC_3324 cis-3-[2-(4-Methyl-piperazin-1-yl)- INT-1026 5-bromo-2-(4-methylpiperazin-1- step 2 of SC_3097 (for synthesis), 1H NMR (DMSO-d6): δ 8.52 (s, 2H), 7.64 518.3 pyrimidin-5-yl]-8-[methyl- yl)pyrimidine SC_3292 and SC_3293 (broad s, 1H), 7.36-7.23 (m, 5H), 3.66-3.55 (tetrahydro-furan-3-yl-methyl- (for separation of enantiomers) (m, 7H), 3.48 (s, 2H), 3.37-3.36 (m, 1H), amino]-8-phenyl-1,3- 2.33-2.13 (m, 11H), 2.01-1.82 (m, 9H), 1.50- diazaspiro[4.5]decan-2-one 1.41 (m, 3H). (enantiomer 2) SC_3325 cis-3-[2-(4-Methyl-piperazin-1-yl)- INT-1026 5-bromo-2-(4-methylpiperazin-1- step 2 of SC_3097 (for synthesis), 1H NMR (DMSO-d6): δ 8.52 (s, 2H), 7.64 518.3 pyrimidin-5-yl]-8-[methyl- yl)pyrimidine SC_3292 and SC_3293 (broad s, 1H), 7.36-7.24 (m, 5H), 3.66-3.55 (tetrahydro-furan-3-yl-methyl- (for separation of enantiomers) (m, 7H), 3.48 (s, 2H), 3.36 (m, 1H), 2.34- amino]-8-phenyl-1,3- 2.13 (m, 10H), 2.01-1.83 (m, 10H), 1.50- diazaspiro[4.5]decan-2-one 1.41 (m, 3H). SC_3326 cis-8-Dimethylamino-3-(4,6- INT-976 4-(5-bromo-4,6-dimethyl-pyrimidin- SC_3103 — 465.3 dimethyl-2-morpholin-4-yl- 2-yl)morpholine pyrimidin-5-yl)-8-phenyl-1,3- diazaspiro[4.5]decan-2-one SC_3327 cis-8-Dimethylamino-3-(2- INT-1027 morpholine SC_3120 1H NMR (600 MHz, DMSO) δ 8.58 (s, 2H), 443.2 morpholin-4-yl-pyrimidin-5-yl)-8- 7.43 (dd, 1H), 7.40-7.32 (m, 1H), 7.07 (dd, thiophen-2-yl-1,3- 1H), 6.96 (dd, 1H), 3.67-3.61 (m, 4H), 3.62- diazaspiro[4.5]decan-2-one 3.57 (m, 6H), 2.31-2.27 (m, 2H), 2.04 (s, 6H), 1.91 (t, 2H), 1.86-1.82 (m, 2H), 1.56- 1.50 (m, 2H). SC_3328 cis-6-(8-Dimethylamino-2-oxo-8- SC_3312 SC_3016 1H NMR (600 MHz, DMSO) δ 8.71 (d, J = 394.2 phenyl-1,3-diazaspiro[4.5]decan-3- 2.3 Hz, 1H), 8.24 (d, J = 8.9 Hz, 1H), 8.12 yl)-pyridine-3-carboxylic acid (dd, J = 9.0, 2.4 Hz, 1H), 7.95 (s, 1H), 7.86 amide (s, 1H), 7.36 (dq, J = 13.7, 6.6, 5.6 Hz, 5H), 7.27 (t, J = 7.2 Hz, 1H), 3.74 (s, 2H), 2.41- 2.37 (m, 2H), 1.96 (s, 6H), 1.94-1.87 (m, 2H), 1.86-1.80 (m, 2H), 1.51-1.44 (m, 2H). SC_3329 cis-8-Dimethylamino-3-[2-methyl- INT-997 5-bromo-1-methyl-3- SC_3319 1H NMR (600 MHz, DMSO) δ 7.66-7.63 428.2 5-(trifluoromethyl)-2H-pyrazol-3- (trifluoromethyl)pyrazole (m, 1H), 7.42 (dd, 1H), 7.06 (dd, 1H), 6.95 yl]-8-thiophen-2-yl-1,3- (dd, 1H), 6.64 (s, 1H), 3.75 (s, 3H), 3.60 (s, diazaspiro[4.5]decan-2-one 2H), 2.30-2.26 (m, 2H), 2.04 (s, 6H), 1.98- 1.90 (m, 2H), 1.83-1.79 (m, 2H), 1.64- 1.57 (m, 2H). SC_3330 cis-8-Dimethylamino-3-[2-[(2- INT-1027 2-(methylamino)ethanol SC_3120 1H NMR (600 MHz, DMSO) δ 8.48 (s, 2H), 431.2 hydroxy-ethyl)-methyl-amino]- 7.43 (d, 1H), 7.30 (s, 1H), 7.07 (dd, 1H), pyrimidin-5-yl]-8-thiophen-2-yl- 6.96 (d, 1H), 3.61 (dd, 2H), 3.58-3.51 (m, 1,3-diazaspiro[4.5]decan-2-one 4H), 3.09 (s, 3H), 2.34-2.22 (m, 2H), 2.04 (s, 6H), 1.96-1.76 (m, 4H), 1.56-1.50 (m, 2H). SC_3331 cis-8-Dimethylamino-3-[2-(2-oxo- INT-1027 4-(4,4,5,5-tetramethyl-1,3,2- SC_3208 1H NMR (600 MHz, DMSO) δ 10.46 (s, 489.2 1,3-dihydro-indol-4-yl)-pyrimidin- dioxaborolan-2-yl)indolin-2-one 1H), 9.12 (s, 2H), 7.87 (d, 1H), 7.47-7.42 5-yl]-8-thiophen-2-yl-1,3- (m, 1H), 7.31 (t, 1H), 7.08 (dd, 1H), 6.98 diazaspiro[4.5]decan-2-one (dd, 1H), 6.92 (d, 1H), 3.83 (s, 2H), 3.77 (s, 2H), 2.35-2.30 (m, 2H), 2.05 (s, 6H), 1.96 (t, 2H), 1.88 (s, 2H), 1.60-1.54 (m, 2H). SC_3332 cis-8-Dimethylamino-3-[4-methyl- INT-976 4-(5-bromo-4-methyl-pyridin-2-yl)- step 2 of SC_3097 1H-NMR (DMSO-d6, 400 MHz at 100° C.), δ 463.2 6-(3-oxo-piperazin-1-yl)-pyridin-3- piperazin-2-one (ppm) = 7.89 (s, 1H), 7.62 (bs, 1H), 7.35- yl]-8-phenyl-1,3- 7.22 (m, 5H), 6.73 (s, 1H), 6.62 (s, 1H), 3.96 diazaspiro[4.5]decan-2-one (s, 2H), 3.68 (t, 2H, J = 5.2 Hz), 3.39 (s, 2H), 3.30 (bs, 2H), 2.35-2.30 (m, 2H), 2.15 (s, 3H), 2.03-1.86 (m, 10H), 1.56-1.51 (m, 2H). SC_3333 cis-8-Dimethylamino-3-(4-methyl- INT-976 5-bromo-2-chloro-4-methyl-pyridine SC_3103 (for step 1), 1H-NMR (DMSO-d6, 400 MHz at 100 0 C.), 442.3 6-pyridin-2-yl-pyridin-3-yl)-8- (step 1), SC_3162 (for step 2) δ (ppm) = 8.64 (d, 1H, J = 4.0 Hz), 8.45 (s, phenyl-1,3-diazaspiro[4.5]decan-2- 2-tributylstannanyl-pyridine 1H), 8.31 (d, 1H, J = 8.68 Hz), 8.22 (s, 1H), one (step 2) 7.88 (t, 1H, J = 7.04 Hz), 7.39-7.35 (m, 5H), 7.26-7.23 (m, 1H), 7.03 (s, 1H), 3.57 (s, 2H), 2.39-2.33 (m, 5H), 2.04 (s, 6H), 2.01-1.88 (m, 4H), 1.61-1.57 (m, 2H). SC_3334 cis-8-Dimethylamino-3-(4- INT-976 3-bromo-4-methylsulfanyl- SC_3103 (for step 1), 1HNMR at 100° C. (DMSO-d6, 400 MHz), δ 429.3 methylsulfonyl-pyridin-3-yl)-8- pyridine (step 1) SC_3008 (for step 2) (ppm) = 8.77-8.72 (m, 2H), 7.85-7.84 (m, phenyl-1,3-diazaspiro[4.5]decan-2- 1H), 7.35-7.23 (m, 6H), 3.60 (s, 2H), 3.31 one (s, 3H), 2.36 (bs, 2H), 2.03-1.82 (m, 10H), 1.60-1.58 (m, 2H). SC_3335 cis-3-(Benzothiazol-7-yl)-8- INT-976 7-bromo-benzothiazole SC_3103 407.1 dimethylamino-8-phenyl-1,3- diazaspiro[4.5]decan-2-one SC_3336 cis-8-Dimethylamino-8-(4- INT-1025 4-(5-bromo-4-methyl- SC_3319 1H NMR (600 MHz, DMSO) δ 8.13 (s, 1H), 469.3 fluorophenyl)-3-(4-methyl-2- pyrimidin-2-yl)morpholine 7.41-7.35 (m, 2H), 7.22-7.13 (m, 3H), morpholin-4-yl-pyrimidin-5-yl)- 3.69-3.60 (m, 8H), 2.35-2.31 (m, 2H), 1,3-diazaspiro[4.5]decan-2-one 2.20 (s, 3H), 1.94 (s, 6H), 1.93-1.74 (m, 4H), 1.53-1.43 (m, 2H). SC_3337 cis-2-[8-Dimethylamino-3-[4- SC_3122 2-chloro-N,N-dimethyl-acetamide INT-988 (step 1) 1H NMR (600 MHz, DMSO) δ 8.59 (s, 1H), 518.3 methyl-6-(trifluoromethyl)-pyridin- 7.82 (s, 1H), 7.37-7.32 (m, 4H), 7.25 (ddd, 3-yl]-2-oxo-8-phenyl-1,3- 1H), 4.00 (s, 2H), 3.80 (s, 2H), 3.07 (s, 3H), diazaspiro[4.5]decan-1-yl]-N,N- 2.87 (s, 3H), 2.71-2.64 (m, 2H), 2.55 (s, dimethyl-acetamide 3H), 2.34 (s, 3H), 2.03 (td, 2H), 1.98 (s, 6H), 1.67-1.58 (m, 2H), 1.49-1.40 (m, 2H). SC_3338 cis-8-Dimethylamino-3-[2-(2- INT-989 2-methyl-4-(4,4,5,5-tetramethyl-1,3,2- SC_3208 1H NMR (600 MHz, DMSO) δ 9.57 (s, 1H), 497.3 methyl-1-oxo-2,3-dihydro-isoindol- dioxaborolan-2-yl)isoindolin-1-one 9.08 (s, 2H), 8.52 (d, 1H), 8.43 (s, 1H), 7.77 4-yl)-pyrimidin-5-yl]-8-phenyl-1,3- (d, 1H), 7.72 (d, 2H), 7.63 (t, 1H), 7.59 (t, diazaspiro[4.5]decan-2-one 2H), 7.55 (t, 1H), 4.86 (s, 2H), 3.59 (s, 2H), 3.13 (s, 3H), 2.72 (d, 2H), 2.61 (s, 6H), 2.25 (td, 2H), 1.91 (d, 2H), 1.43-1.35 (m, 2H). SC_3339 cis-2-[[5-(8-Dimethylamino-2-oxo- INT-976 (5-bromo-2-methyl-pyrimidin-4- step 2 of SC_3242 (for step 1), ¹HNMR at 100° C. (DMSO-d6, 400 MHz), δ 438.4 8-phenyl-1,3-diazaspiro[4.5]decan- ylamino)-acetonitrile (step 1) SC_3016 (for step 2) (ppm) = 7.93 (s, 1H), 7.36-7.22 (m, 5H), 3-yl)-2-methyl-pyrimidin-4- 7.12 (s, 1H), 6.91 (bs, 2H), 6.58 (bs, 1H), yl]amino]-acetamide 3.94 (d, 2H), 3.46 (s, 2H), 2.35-2.32 (m, 5H), 2.03-1.97 (m, 8H), 1.91-1.84 (m, 2H), 1.61- 1.56 (m, 2H). SC_3341 cis-8-Dimethylamino-3-[4- INT-976 3-bromo-4- step 2 of SC_3097 1HNMR at 100° C. (DMSO-d6, 400 MHz), δ 443.4 (methylsulfonyl-methyl)-pyridin-3- methanesulfonylmethyl-pyridine (ppm) = 8.53 (s, 1H), 8.43 (d, 1H, J = 4.88 yl]-8-phenyl-1,3- Hz), 7.48 (d, 1H, J = 4.88 Hz), 7.36-7.23 (m, diazaspiro[4.5]decan-2-one 5H), 7.15 (s, 1H), 4.55 (s, 2H), 3.64 (s, 2H), 2.95 (s, 3H), 2.38-2.33 (m, 2H), 2.04 (s, 6H), 1.99-1.83 (m, 4H), 1.62-1.57 (m, 2H). SC_3342 cis-8-Dimethylamino-3-[6-(4- INT-976 4-(5-bromo-2-pyridyl)-1-methyl- SC_3242 (step 2) 1H NMR (600 MHz, CDCl3) δ 8.09 (d, 1H), 463.3 methyl-3-oxo-piperazin-1-yl)- piperazin-2-one 8.00 (dd, 1H), 7.45-7.39 (m, 2H), 7.37- pyridin-3-yl]-8-phenyl-1,3- 7.28 (m, 3H), 6.61 (d, 1H), 5.71 (s, 1H), 4.04 diazaspiro[4.5]decan-2-one (s, 2H), 3.87-3.82 (m, 2H), 3.51 (s, 2H), 3.45 (t, 2H), 3.03 (s, 3H), 2.32-2.02 (m, 10H), 2.02-1.94 (m, 2H), 1.64-1.53 (m, 2H). SC_3343 cis-8-Dimethylamino-3-(2,4- INT-976 5-bromo-2,4-dimethyl-pyrimidine SC_3103 1H NMR (600 MHz, DMSO) δ 8.46 (s, 1H), 380.3 dimethyl-pyrimidin-5-yl)-8-phenyl- 7.45-7.33 (m, 5H), 7.28-7.24 (m, 1H), 1,3-diazaspiro[4.5]decan-2-one 3.51 (s, 2H), 2.54 (s, 3H), 2.41-2.28 (m, 5H), 2.03-1.77 (m, 10H), 1.56-1.49 (m, 2H). SC_3344 cis-8-Dimethylamino-3-[2-(1-oxo- INT-989 4-(4,4,5,5-tetramethyl-1,3,2- SC_3208 1H NMR (600 MHz, DMSO) δ 9.06 (s, 2H), 483.3 2,3-dihydro-isoindol-4-yl)- dioxaborolan-2-yl)isoindolin-1-one 8.67 (s, 1H), 8.52 (d, 1H), 8.39 (s, 1H), 7.75 pyrimidin-5-yl]-8-phenyl-1,3- (dd, 3H), 7.66-7.51 (m, 4H), 4.75 (s, 2H), diazaspiro[4.5]decan-2-one; 2,2,2- 3.58 (s, 2H), 3.18 (s, 2H), 2.75 (d, 2H), 2.60 trifluoro-acetic acid (s, 6H), 2.27 (t, 2H), 1.91 (d, 2H), 1.39 (t, 2H). SC_3345 cis-8-Dimethylamino-3-[6-[(2- INT-976 2-[[5-bromo-3-(trifluoromethyl)-2- SC_3103 1H NMR (600 MHz, DMSO) δ 8.55-8.51 492.3 hydroxy-ethyl)-methyl-amino]-5- pyridyl]-methyl-amino]ethanol (m, 1H), 8.35 (d, 1H), 7.62 (s, 1H), 7.37 (td, (trifluoromethyl)-pyridin-3-yl]-8- 4H), 7.27 (td, 1H), 3.63 (s, 2H), 3.50 (td, phenyl-1,3-diazaspiro[4.5]decan-2- 2H), 3.20 (t, 2H), 2.78 (s, 3H), 2.43-2.36 one (m, 2H), 1.96 (s, 6H), 1.95-1.75 (m, 4H), 1.48 (t, 2H). SC_3346 cis-8-Dimethylamino-8-phenyl-3- INT-976 3,3,3-trifluoroprop-1-yne, SC_3313 1H NMR (600 MHz, DMSO) δ 9.56 (d, 1H), 487.3 [2-[4-(trifluoromethyl)-1H- 2-azido-5-bromo-pyrimidine 9.16 (s, 2H), 7.99 (s, 1H), 7.42-7.35 (m, [1,2,3]triazol-1-yl]-pyrimidin-5-yl]- 4H), 7.31-7.25 (m, 1H), 3.75 (s, 2H), 2.49- 1,3-diazaspiro[4.5]decan-2-one 2.34 (m, 2H), 2.05-1.75 (m, 10H), 1.60- 1.47 (m, 2H). SC_3347 cis-8-Dimethylamino-3-[2-(4- INT-976 3-methylbut-1-yne, SC_3313 1H NMR (600 MHz, DMSO) δ 9.10 (s, 2H), 461.3 isopropyl-1H-[1,2,3]triazol-1-yl)- 2-azido-5-bromo-pyrimidine 8.50 (d, 1H), 7.91 (s, 1H), 7.42-7.35 (m, pyrimidin-5-yl]-8-phenyl-1,3- 5H), 7.28 (td, 1H), 3.73 (s, 2H), 3.08 (hept, diazaspiro[4.5]decan-2-one 1H), 2.44 (s, 2H), 2.01-1.76 (m, 10H), 1.59- 1.48 (m, 2H), 1.30 (d, 6H). SC_3348 cis-8-Dimethylamino-3-[6-(1,1- INT-976 1,4-thiazinane 1,1-dioxide, SC_3242 1H NMR (600 MHz, DMSO) δ 8.23 (d, 1H), 484.2 dioxo-[1,4]thiazinan-4-yl)-pyridin- 5-bromo-2-chloro-pyridine (step 1) 7.93 (dd, 1H), 7.41-7.33 (m, 5H), 7.27 (t, 3-yl]-8-phenyl-1,3- 1H), 6.98 (d, 1H), 3.97 (t, 4H), 3.53 (s, 2H), diazaspiro[4.5]decan-2-one 3.04 (t, 4H), 2.43-2.28 (m, 2H), 1.96 (s, 6H), 1.92-1.72 (m, 4H), 1.51-1.40 (m, 2H). SC_3349 cis-5-(8-Dimethylamino-2-oxo-8- INT-976 5-bromo-2-chloropyridine-3- SC_3242 1H NMR (600 MHz, DMSO-d6) δ 8.66 (d, 461.3 phenyl-1,3-diazaspiro[4.5]decan-3- carbonitrile, morpholine J = 2.9 Hz, 1H), 8.25 (d, J = 2.8 Hz, 1H), 7.60 yl)-2-morpholin-4-yl-nicotinonitrile (s, 1H), 7.41-7.33 (m, 4H), 7.30-7.24 (m, 1H), 3.74-3.69 (m, 4H), 3.60 (s, 2H), 2.48- 2.29 (m, 2H), 1.96 (s, 6H), 1.94-1.68 (m, 4H), 1.52-1.41 (m, 2H). SC_3350 cis-8-Dimethylamino-3-(1- INT-976 5-bromo-1-methylsulfonyl- SC_3103 1H NMR (600 MHz, DMSO) δ 8.64 (d, 1H), 468.2 methylsulfonyl-1H-pyrrolo[2,3- pyrrolo[2,3-b]pyridine 8.28 (d, 1H), 7.65 (dd, 1H), 7.57 (s, 1H), b]pyridin-5-yl)-8-phenyl-1,3- 7.38 (dd, 4H), 7.28 (dt, 1H), 6.72 (dd, 1H), diazaspiro[4.5]decan-2-one 3.68 (s, 2H), 3.65 (s, 3H), 2.48-2.29 (m, 2H), 1.98 (s, 10H), 1.53-1.44 (m, 2H). SC_3351 cis-8-Dimethylamino-3-(1H-indol- INT-976 4-bromo-1-(toluene- SC_3357 1H-NMR (DMSO-d6, 400 MHz at 100 0 C.), 389.3 4-yl)-8-phenyl-1,3- 4-sulfonyl)-1H-indole (step 1) δ (ppm) = 10.77 (bs, 1H), 7.37 (bs, 4H), diazaspiro[4.5]decan-2-one 7.24-7.18 (m, 3H), 7.02-6.94 (m, 2H), 6.81 (bs, 1H), 6.41 (s, 1H), 3.66 (s, 2H), 2.36-2.33 (m, 2H), 2.05-1.96 (m, 10H), 1.60-156 (m, 2H). SC_3353 cis-8-Dimethylamino-3-[2-fluoro- INT-976 1-bromo-2-fluoro-4- SC_3103 1H NMR (600 MHz, DMSO) δ 7.62 (t, 1H), 452.2 4-(trifluoromethyloxy)-phenyl]-8- (trifluoromethoxy)-benzene 7.50-7.46 (m, 1H), 7.40 (dd, 1H), 7.38- phenyl-1,3-diazaspiro[4.5]decan-2- 7.31 (m, 4H), 7.25 (t, 1H), 7.21 (d, 1H), 3.57 one (s, 2H), 2.38 (d, 2H), 1.97-1.88 (m, 8H), 1.84-1.79 (m, 2H), 1.53-1.46 (m, 2H). SC_3355 cis-8-Dimethylamino-3-(1-methyl- INT-976 4-bromo-1-methyl-pyrrolo[2,3- SC_3103 1H NMR (600 MHz, DMSO) δ 8.04 (d, 1H), 404.3 1H-pyrrolo[2,3-b]pyridin-4-yl)-8- b]pyridine 7.70 (s, 1H), 7.47 (d, 1H), 7.41-7.33 (m, phenyl-1,3-diazaspiro[4.5]decan-2- 4H), 7.31-7.24 (m, 2H), 6.65 (d, 1H), 3.91 one (s, 2H), 3.74 (s, 3H), 2.44-2.25 (m, 2H), 2.08-1.74 (m, 10H), 1.52 (t, 2H). SC_3356 cis-3-(1-Acetyl-1H-indol-4-yl)-8- SC_3351 acetyl chloride SC_3379 1H-NMR (DMSO-d6, 400 MHz at 100 0 C.), 431.2 dimethylamino-8-phenyl-1,3- δ (ppm) = 8.12 (d, 1H, J = 8.28 Hz), 7.68 (d, diazaspiro[4.5]decan-2-one 1H, J = 3.64 Hz), 7.36-7.22 (m, 6H), 7.16 (d, 1H, J = 7.80 Hz), 7.01 (s, 1H), 6.69 (d, 1H, J = 3.8 Hz), 3.66 (s, 2H), 2.62 (s, 3H), 2.38- 2.33 (m, 2H), 2.05-1.92 (m, 10H), 1.61-1.56 (m, 2H). SC_3358 cis-6-(8-Dimethylamino-2-oxo-8- INT-976 6-chloro-5-methyl-pyridine-3- SC_3103 1H NMR (600 MHz, DMSO) δ 8.64 (s, 1H), 390.2 phenyl-1,3-diazaspiro[4.5]decan-3- carbonitrile 8.12 (s, 1H), 7.76 (s, 1H), 7.39-7.34 (m, yl)-5-methyl-nicotinonitrile 4H), 7.27 (s, 1H), 3.71 (s, 2H), 2.43-2.15 (m, 5H), 2.11-1.70 (m, 10H), 1.52 (s, 2H). SC_3359 cis-6-(8-Dimethylamino-2-oxo-8- INT-976 6-chloro-5-fluoro-pyridine-3- SC_3103 1H NMR (600 MHz, DMSO) δ 8.64 (d, 1H), 394.2 phenyl-1,3-diazaspiro[4.5]decan-3- carbonitrile 8.30 (dd, 1H), 7.95 (s, 1H), 7.40-7.31 (m, yl)-5-fluoro-nicotinonitrile 4H), 7.29-7.23 (m, 1H), 3.72 (s, 2H), 2.36- 2.33 (m, 2H), 1.96 (s, 6H), 1.94-1.79 (m, 4H), 1.52 (t, 2H). SC_3361 cis-6-(8-Dimethylamino-2-oxo-8- SC_3358 SC_3016 1H NMR (600 MHz, DMSO) δ 8.64 (d, 1H), 408.2 phenyl-1,3-diazaspiro[4.5]decan-3- 8.06-8.02 (m, 2H), 7.54 (s, 1H), 7.44 (s, yl)-5-methyl-pyridine-3-carboxylic 1H), 7.38-7.30 (m, 4H), 7.27-7.21 (m, acid amide 1H), 3.67 (s, 2H), 2.37-2.26 (m, 5H), 2.05- 1.75 (m, 10H), 1.51 (t, 2H). SC_3362 cis-6-(8-Dimethylamino-2-oxo-8- SC_3359 SC_3016 1H NMR (600 MHz, DMSO) δ 8.65-8.61 412.2 phenyl-1,3-diazaspiro[4.5]decan-3- (m, 1H), 8.13 (s, 1H), 8.04 (dd, 1H), 7.76 (s, yl)-5-fluoro-pyridine-3-carboxylic 1H), 7.59 (s, 1H), 7.39-7.30 (m, 4H), 7.28- acid amide 7.21 (m, 1H), 3.70 (s, 2H), 2.41-2.23 (m, 2H), 1.96-1.76 (m, 10H), 1.50 (t, 2H). SC_3363 cis-8-Dimethylamino-3-[4-methyl- INT-1038 5-bromo-4-methyl-2- SC_3319 1H NMR (600 MHz, DMSO) δ 8.56 (s, 1H), 447.2 6-(trifluoromethyl)-pyridin-3-yl]-8- (trifluoromethyl)pyridine 7.80 (s, 1H), 7.52 (s, 1H), 7.24 (t, 1H), 7.17- m-tolyl-1,3-diazaspiro[4.5]decan-2- 7.11 (m, 2H), 7.06 (d, 1H), 3.60 (s, 2H), one 2.39-2.25 (m, 8H), 2.01-1.78 (m, 10H), 1.58-1.48 (m, 2H). SC_3364 cis-3-(8-Dimethylamino-2-oxo-8- INT-976 3-bromopyridine-4-carbonitrile SC_3242 1H NMR (600 MHz, DMSO) δ 8.79 (s, 1H), 376.2 phenyl-1,3-diazaspiro[4.5]decan-3- 8.50 (d, 1H), 7.84-7.80 (m, 1H), 7.37 (td, yl)-isonicotinonitrile 4H), 7.26 (td, 1H), 3.79 (s, 2H), 2.43-2.36 (m, 2H), 1.97 (s, 7H), 1.96-1.91 (m, 2H), 1.88-1.81 (m, 2H), 1.61-1.45 (m, 2H). SC_3365 cis-8-Dimethylamino-3-[3-fluoro- INT-1045 4-(4,4,5,5-tetramethyl-1,3,2- SC_3354 1H NMR (600 MHz, DMSO) δ 10.51 (s, 500.2 5-(2-oxo-1,3-dihydro-indol-4-yl)- dioxaborolan-2-yl)indolin-2-one 1H), 8.39 (d, 1H), 7.96 (dd, 1H), 7.41-7.32 pyridin-2-yl]-8-phenyl-1,3- (step 2) (m, 4H), 7.28 (dt, 2H), 7.08 (d, 1H), 6.88 (d, diazaspiro[4.5]decan-2-one 1H), 3.71 (s, 2H), 3.67 (s, 2H), 2.44-2.22 (m, 2H), 1.98-1.87 (m, 11H), 1.58-1.46 (m, 2H). SC_3366 cis-8-Dimethylamino-3-[4-methyl- INT-1039 5-bromo-4-methyl-2- SC_3319 1H NMR (600 MHz, DMSO) δ 8.55 (s, 1H), 517.2 6-(trifluoromethyl)-pyridin-3-yl]-8- (trifluoromethyl)pyridine 7.79 (s, 1H), 7.51 (t, 2H), 7.38 (dd, 1H), 7.26 [3-(trifluoromethyloxy)-phenyl]- (d, 2H), 3.62 (s, 2H), 2.40-2.34 (m, 2H), 1,3-diazaspiro[4.5]decan-2-one 2.31 (s, 3H), 2.01-1.77 (m, 10H), 1.58- 1.49 (m, 2H). SC_3367 cis-8-Dimethylamino-3-[4-methyl- INT-1040 5-bromo-4-methyl-2- SC_3319 1H NMR (600 MHz, DMSO) δ 8.55 (s, 1H), 501.2 6-(trifluoromethyl)-pyridin-3-yl]-8- (trifluoromethyl)pyridine 7.79 (s, 1H), 7.69-7.56 (m, 5H), 7.52 (s, [3-(trifluoromethyl)phenyl]-1,3- 1H), 3.61 (s, 2H), 2.44-2.36 (m, 2H), 2.31 diazaspiro[4.5]decan-2-one (s, 3H), 2.02-1.80 (m, 10H), 1.60-1.47 (m, 2H). SC_3368 cis-8-Dimethylamino-8-(3- INT-1041 5-bromo-4-methyl-2- SC_3319 1H NMR (600 MHz, DMSO) δ 8.56 (s, 1H), 463.2 methoxyphenyl)-3-[4-methyl-6- (trifluoromethyl)pyridine 7.80 (s, 1H), 7.51 (s, 1H), 7.31-7.25 (m, (trifluoromethyl)-pyridin-3-yl]-1,3- 1H), 6.92 (dt, 1H), 6.87-6.82 (m, 2H), 3.75 diazaspiro[4.5]decan-2-one (s, 3H), 3.61 (s, 2H), 2.35-2.30 (m, 5H), 1.98 (s, 7H), 1.96-1.90 (m, 2H), 1.88- 1.80 (m, 2H), 1.60-1.49 (m, 2H). SC_3369 cis-8-(5-Chloro-thiophen-2-yl)-8- INT-1042 5-bromo-4-methyl-2- SC_3319 1H NMR (600 MHz, DMSO) δ 8.56 (s, 1H), 473.1 dimethylamino-3-[4-methyl-6- (trifluoromethyl)pyridine 7.79 (s, 1H), 7.39 (s, 1H), 7.04-7.00 (m, (trifluoromethyl)-pyridin-3-yl]-1,3- 1H), 6.80 (d, 1H), 3.64 (s, 2H), 2.31 (s, 3H), diazaspiro[4.5]decan-2-one 2.22-2.15 (m, 2H), 2.04 (s, 6H), 1.95- 1.87 (m, 2H), 1.83-1.77 (m, 2H), 1.63- 1.57 (m, 2H). SC_3370 cis-8-Dimethylamino-8-(3- INT-1024 5-bromo-4-methyl-2- SC_3319 1H NMR (600 MHz, DMSO) δ 8.56 (s, 1H), 451.2 fluorophenyl)-3-[4-methyl-6- (trifluoromethyl)pyridine 7.80 (s, 1H), 7.51 (s, 1H), 7.41 (td, 1H), 7.21- (trifluoromethyl)-pyridin-3-yl]-1,3- 7.12 (m, 2H), 7.12-7.06 (m, 1H), 3.61 (s, diazaspiro[4.5]decan-2-one 2H), 2.38-2.30 (m, 5H), 1.97 (s, 6H), 1.96- 1.90 (m, 2H), 1.90-1.73 (m, 2H), 1.61- 1.45 (m, 2H). SC_3371 cis-8-Dimethylamino-3-(2- INT-989 methylamine SC_3239 1H NMR (600 MHz, DMSO + TFA) δ 8.69 381.2 methylamino-pyrimidin-5-yl)-8- (s, 2H), 8.29 (s, 1H), 7.68 (d, 2H), 7.52 (dt, phenyl-1,3-diazaspiro[4.5]decan-2- 3H), 2.90 (s, 3H), 2.68 (d, 2H), 2.59 (s, 6H), one 2.24 (t, 2H), 1.86 (d, 2H), 1.39-1.31 (m, 2H) SC_3372 cis-8-(5-Chloro-thiophen-2-yl)-8- INT-1042 4-(5-bromo-4-methyl- SC_3242 1H NMR (600 MHz, DMSO) δ 8.15 (d, 1H), 491.2 dimethylamino-3-(4-methyl-2- pyrimidin-2-yl)morpholine 7.15 (s, 1H), 7.05 (d, 1H), 6.82 (d, 1H), 3.70- morpholin-4-yl-pyrimidin-5-yl)- 3.61 (m, 8H), 3.44 (s, 2H), 2.31-2.12 (m, 1,3-diazaspiro[4.5]decan-2-one 5H), 2.06 (s, 6H), 1.93-1.85 (m, 2H), 1.82- 1.69 (m, 2H), 1.64-1.49 (m, 2H). SC_3373 cis-N-[5-(8-Dimethylamino-2-oxo- SC_3371 Cyclopropancarbonyl chlorid SC_3240 1H NMR (600 MHz, DMSO) δ 8.97 (s, 2H), 449.3 8-phenyl-1,3-diazaspiro[4.5]decan- 7.83-7.73 (m, 1H), 7.41-7.34 (m, 4H), 3-yl)-pyrimidin-2-yl]-N-methyl- 7.30-7.24 (m, 1H), 3.66 (s, 2H), 3.27 (s, cyclopropanecarboxylic acid amide 3H), 2.47-2.29 (m, 2H), 1.99-1.87 (m, 10H), 1.49 (t, 2H), 0.88-0.80 (m, 2H), 0.70 (dt, 2H). SC_3374 cis-N-[5-(8-Dimethylamino-2-oxo- SC_3371 2,5-dimethylpyrazole-3-carbonyl SC_3240 1H NMR (600 MHz, DMSO) δ 8.83 (s, 2H), 503.3 8-phenyl-1,3-diazaspiro[4.5]decan- chloride 7.77 (s, 1H), 7.41-7.32 (m, 4H), 7.27 (td, 3-yl)-pyrimidin-2-yl]-N,2,5- 1H), 5.48 (s, 1H), 3.80 (s, 3H), 3.61 (s, 2H), trimethyl-2H-pyrazole-3-carboxylic 3.40 (s, 3H), 2.46-2.31 (m, 2H), 1.96 (s, acid amide 3H), 1.96 (s, 6H), 1.94-1.74 (m, 5H), 1.52- 1.42 (m, 2H). SC_3375 cis-3-[4,6-Bis(trifluoromethyl)- INT-976 5-bromo-2,4- SC_3103 1H NMR (600 MHz, DMSO) δ 8.98 (s, 1H), 487.2 pyridin-3-yl]-8-dimethylamino-8- bis(trifluoromethyl)pyridine 8.20 (s, 1H), 7.79 (s, 1H), 7.40-7.32 (m, phenyl-1,3-diazaspiro[4.5]decan-2- 4H), 7.26 (td, 1H), 3.62 (s, 2H), 2.44-2.24 one (m, 2H), 1.98-1.91 (m, 8H), 1.86 (s, 2H), 1.53 (t, 2H). SC_3376 cis-8-Dimethylamino-3-[2-[(2- INT-976 2-[(6-bromo-quinazolin-2-yl)- SC_3242 1HNMR at 100° C. (DMSO-d6, 400 MHz), δ 475.1 hydroxy-ethyl)-methyl-amino]- methyl-amino]-ethanol (ppm) = 8.99 (s, 1H), 8.28 (d, 1H, J = 9.24 quinazolin-6-yl]-8-phenyl-1,3- Hz), 7.63 (s, 1H), 7.43-7.26 (m, 6H), 7.13 diazaspiro[4.5]decan-2-one (s, 1H), 4.31 (bs, 1H), 3.78-3.76 (m, 2H), 3.66 (bs, 4H), 3.24 (s, 3H), 2.43-2.38 (m, 2H), 2.05-1.90 (m, 10H), 1.56-1.54 (m, 2H). SC_3377 cis-8-Dimethylamino-3-(2- INT-976 6-bromo-2-morpholin-4-yl- SC_3242 1HNMR at 100° C. (DMSO-d6, 400 MHz), δ 487.2 morpholin-4-yl-quinazolin-6-yl)-8- quinazoline (ppm) = 9.05 (s, 1H), 8.34 (d, 1H), 7.68 (s, phenyl-1,3-diazaspiro[4.5]decan-2- 1H), 7.48 (d, 1H, J = 9.4 Hz), 7.38-7.27 (m, one 5H), 7.18 (s, 1H), 3.81-3.67 (m, 10H), 2.40- 2.38 (m, 2H), 2.05-1.90 (m, 10H), 1.57-1.54 (m, 2H). SC_3378 cis-8-[Methyl-(oxetan-3-yl- INT-1047 2-trifluoromethyl-5- SC_3103 1H NMR (DMSO-d6): δ 9.21-9.15 (s, 2H), 476.2 methyl)-amino]-8-phenyl-3-[2- bromopyrimidine 8.19-8.18 (broad s, 1H), 7.41-7.34 (m, 4H), (trifluoromethyl)-pyrimidin-5-yl]- 7.27-7.25 (m, 1H), 4.58-4.56 (m, 2H), 4.18 1,3-diazaspiro[4.5]decan-2-one (s, 1H), 3.69 (s, 2H), 3.05-2.99 (m, 1H), 2.41-2.36 (m, 4H), 1.91 (m, 7H), 1.47 (s, 2H). SC_3380 cis-8-Dimethylamino-8-phenyl-3- INT-976 6-bromo-quinazoline SC_3103 1HNMR at 100° C. (DMSO-d6, 400 MHz), δ 402.2 quinazolin-6-yl-1,3- (ppm) = 9.35 (s, 1H), 9.10 (s, 1H), 8.65 diazaspiro[4.5]decan-2-one (d, 1H, J = 9.04) 7.91-7.89 (m, 2H), 7.39- 7.27 (m, 5H), 3.75 (s, 2H), 2.42-2.32 (m, 2H), 2.05 (s, 6H), 2.00-1.92 (m, 4H), 1.56 (bs, 2H). SC_3381 cis-5-(8-Dimethylamino-2-oxo-8- INT-976 5-bromo-2-chloro- SC_3103 (for step 1), 1H NMR (600 MHz, DMSO) δ 8.88 (s, 1H), 507.3 phenyl-1,3-diazaspiro[4.5]decan-3- pyridine-4-carbonitrile (step 1), SC_3129 (for step 2) 8.24 (s, 1H), 7.85 (s, 1H), 7.52-7.46 (m, yl)-2-(2-oxo-1,3-dihydro-indol-4- 4-(4,4,5,5-tetramethyl-1,3,2- 1H), 7.41-7.29 (m, 6H), 7.27 (td, 1H), 6.92 yl)-isonicotinonitrile dioxaborolan-2- (d, 1H), 3.84 (s, 2H), 3.78 (s, 2H), 2.48- yl)indolin-2-one (step 2) 2.30 (m, 2H), 1.99-1.93 (m, 8H), 1.92- 1.74 (m, 2H), 1.58-1.54 (m, 2H). SC_3382 cis-N-[5-(8-Dimethylamino-2-oxo- SC_3371 tetrahydropyran-4-carbonyl SC_3240 1H NMR (600 MHz, DMSO) δ 8.97 (s, 2H), 493.3 8-phenyl-1,3-diazaspiro[4.5]decan- chloride 7.80 (s, 1H), 7.42-7.34 (m, 4H), 7.31- 3-yl)-pyrimidin-2-yl]-N-methyl- 7.25 (m, 1H), 3.79 (ddd, 2H), 3.67 (s, 2H), tetrahydro-pyran-4-carboxylic acid 3.25 (s, 2H), 3.17 (td, 2H), 3.04-2.96 (m, amide 1H), 2.49-2.34 (m, 2H), 1.97 (s, 6H), 1.95- 1.74 (m, 4H), 1.68-1.53 (m, 4H), 1.54- 1.48 (m, 2H). SC_3383 cis-N-[5-(8-Dimethylamino-2-oxo- SC_3371 pivaloyl chloride SC_3240 1H NMR (600 MHz, DMSO) δ 8.98 (s, 2H), 465.3 8-phenyl-1,3-diazaspiro[4.5]decan- 7.42-7.34 (m, 4H), 7.30-7.26 (m, 1H), 3-yl)-pyrimidin-2-yl]-N,2,2- 3.69 (s, 2H), 3.14 (s, 3H), 2.46-2.41 (m, trimethyl-propionamide 2H), 1.99-1.87 (m, 10H), 1.54-1.45 (m, 2H), 0.97 (s, 9H). SC_3384 cis-8-Dimethylamino-3-[2-(1- INT-989 1-methyl-4-(4,4,5,5- SC_3208 1H NMR (600 MHz, CDCl3) δ 9.05 (s, 2H), 497.3 methyl-2-oxo-1,3-dihydro-indol-4- tetramethyl-1,3,2- 8.08 (d, 1H), 7.47-7.39 (m, 3H), 7.38- yl)-pyrimidin-5-yl]-8-phenyl-1,3- dioxaborolan-2- 7.31 (m, 3H), 6.91 (d, 1H), 5.46 (s, 1H), 4.04 diazaspiro[4.5]decan-2-one yl)indolin-2-one (s, 2H), 3.64 (s, 2H), 3.27 (s, 3H), 2.35- 2.14 (m, 4H), 2.10 (s, 6H), 2.08-2.01 (m, 3H), 1.73-1.64 (m, 2H), 1.28 (s, 0H). SC_3385 cis-8-Dimethylamino-3-(2- INT-976 6-bromo-1-(tert-butylsilanyl- SC_3242 (for step 1), 1HNMR at 100° C. (DMSO-d6, 400 MHz), δ 475.2 morpholin-4-yl-1H-benzoimidazol- methoxymethyl)-2- step 2 of SC_3352 (for step 2) (ppm) = 10.94 (bs, 1H), 7.50 (bs, 1H), 7.39- 5-yl)-8-phenyl-1,3- morpholin-4-yl-1H- 7.27 (m, 5H), 7.06 (m, 2 H), 6.84 (bs, 1H), diazaspiro[4.5]decan-2-one benzoimidazole (step 1) 3.72 (t, 4H, 4.56 Hz), 3.55 (s, 2H), 3.45 (t, 4H, 4.56 Hz), 2.372.24 (m, 2H), 1.95-1.81 (m, 10H), 1.52-1.50 (m, 2H) SC_3386 cis-8-Dimethylamino-8-(3-fluoro- INT-1043 5-bromo-4-methyl-2- SC_3319 1H NMR (600 MHz, DMSO) δ 8.57 (s, 1H), 465.2 5-methyl-phenyl)-3-[4-methyl-6- (trifluoromethyl)pyridine 7.80 (s, 1H), 7.51 (s, 1H), 6.99 (s, 1H), 6.96- (trifluoromethyl)-pyridin-3-yl]-1,3- 6.89 (m, 2H), 3.61 (s, 2H), 2.34 (s, 3H), diazaspiro[4.5]decan-2-one 2.32 (s, 3H), 2.07 (s, 1H), 1.97 (s, 6H), 1.96- 1.89 (m, 2H), 1.88-1.78 (m, 2H), 1.54 (d, 2H). SC_3387 cis-8-Dimethylamino-3-[6-(2-oxo- INT-1048 4-(4,4,5,5-tetramethyl-1,3,2- SC_3129 1H NMR (600 MHz, DMSO) δ 8.83 (d, 1H), 482.3 1,3-dihydro-indol-4-yl)-pyridin-3- dioxaborolan-2-yl)indolin-2-one 8.11 (dd, 1H), 7.77 (d, 1H), 7.64 (s, 1H), yl]-8-phenyl-1,3- 7.43-7.34 (m, 5H), 7.31-7.24 (m, 2H), diazaspiro[4.5]decan-2-one 6.84 (d, 1H), 3.73 (s, 2H), 3.68 (s, 2H), 2.45- 2.31 (m, 2H), 1.99-1.79 (m, 10H), 1.51 (t, 2H). SC_3389 cis-3-[6-(Azetidin-1-yl)-5- INT-976 5-bromo-2-chloro-3- SC_3103 (for step 1), 1H NMR (600 MHz, DMSO) δ 8.40 (d, 1H), 453.2 (trifluoromethyl)-pyridin-3-yl]-8- (trifluoromethyl)pyridine (step 1), SC_3120 (for step 2, 160° C.) 8.21 (d, 1H), 7.47 (s, 1H), 7.41-7.33 (m, dimethylamino-8-phenyl-1,3- azetidine (step 2) 4H), 7.30-7.24 (m, 1H), 4.03 (t, 4H), 3.58 diazaspiro[4.5]decan-2-one (s, 2H), 2.47-2.29 (m, 2H), 2.25 (p, 2H), 1.96 (s, 6H), 1.89 (s, 4H), 1.47 (t, 2H). SC_3390 cis-3-[1-(Cyclopropyl-methyl)-8- SC_3364 bromomethylcyclopropane INT-952 1H NMR (600 MHz, DMSO) δ 8.82 (s, 1H), 430.3 dimethylamino-2-oxo-8-phenyl- 8.51 (dd, 1H), 7.81 (d, 1H), 7.40-7.33 (m, 1,3-diazaspiro[4.5]decan-3-yl]- 4H), 7.29-7.23 (m, 1H), 3.93 (s, 2H), 3.10 isonicotinonitrile (d, 2H), 2.76-2.70 (m, 2H), 2.29 (ddd, 2H), 2.02 (s, 6H), 1.58 (d, 2H), 1.52-1.44 (m, 2H), 1.01 (ddt, 1H), 0.55-0.49 (m, 2H), 0.37-0.31 (m, 2H). SC_3391 cis-3-[3,5-Bis(trifluoromethyl)- INT-976 2-chloro-3,5- SC_3103 1H NMR (600 MHz, DMSO) δ 9.04 (d, 1H), 487.2 pyridin-2-yl]-8-dimethylamino-8- bis(trifluoromethyl)pyridine 8.58 (d, 1H), 7.96 (s, 1H), 7.41-7.32 (m, phenyl-1,3-diazaspiro[4.5]decan-2- 4H), 7.29-7.23 (m, 1H), 3.75 (s, 2H), 2.41- one 2.25 (m, 2H), 1.98-1.89 (m, 10H), 1.52 (t, 2H). SC_3392 cis-8-Dimethylamino-3-(5-fluoro- INT-976 4-(5-bromo-3-fluoro- SC_3103 1H NMR (600 MHz, CDCl3) δ 8.13 (dd, 454.3 6-morpholin-4-yl-pyridin-3-yl)-8- 2-pyridyl)morpholine 1H), 7.76 (d, 1H), 7.42 (t, 2H), 7.33 (dd, phenyl-1,3-diazaspiro[4.5]decan-2- 3H), 5.84 (s, 1H), 3.84 (t, 4H), 3.52 (s, 2H), one 3.37 (t, 4H), 2.29-2.12 (m, 4H), 2.08 (s, 6H), 2.01-1.94 (m, 2H), 1.60 (t, 2H). SC_3393 cis-8-(3-Chlorophenyl)-8- INT-1044 5-bromo-4-methyl-2- SC_3319 1H NMR (600 MHz, DMSO) δ 8.57 (s, 1H), 467.2 dimethylamino-3-[4-methyl-6- (trifluoromethyl)pyridine 7.80 (s, 1H), 7.55-7.49 (m, 1H), 7.43- (trifluoromethyl)-pyridin-3-yl]-1,3- 7.37 (m, 1H), 7.38-7.29 (m, 3H), 3.61 (s, diazaspiro[4.5]decan-2-one 2H), 2.40-2.24 (m, 5H), 1.99-1.90 (m, 8H), 1.90-1.76 (m, 2H), 1.60-1.47 (m, 2H). SC_3394 cis-8-Dimethylamino-3-[5-(2-oxo- INT-1049 4-(4,4,5,5-tetramethyl-1,3,2- SC_3354 1H NMR (600 MHz, DMSO) δ 8.41 (d, 1H), 482.3 1,3-dihydro-indol-4-yl)-pyridin-2- dioxaborolan-2-yl)indolin-2-one 8.26 (d, 1H), 7.92 (dd, 1H), 7.75 (s, 1H), yl]-8-phenyl-1,3- 7.41-7.32 (m, 5H), 7.30-7.23 (m, 2H), diazaspiro[4.5]decan-2-one 7.01 (d, 1H), 6.83 (d, 1H), 3.75 (s, 2H), 3.61 (s, 2H), 2.46-2.30 (m, 2H), 1.96 (s, 6H), 1.94-1.88 (m, 2H), 1.86-1.82 (m, 2H), 1.48 (t, 2H). SC_3395 cis-8-Dimethylamino-8-phenyl-3- INT-976 2-bromo-5-(trifluoromethyl)- SC_3103 1H NMR (600 MHz, DMSO) δ 8.69 (s, 1H), 426.2 [5-(trifluoromethyl)- 1,3,4-thiadiazole 7.42-7.34 (m, 4H), 7.28 (t, 1H), 3.89 (s, [1,3,4]thiadiazol-2-yl]-1,3- 2H), 2.45-2.31 (m, 2H), 2.07-1.88 (m, diazaspiro[4.5]decan-2-one 8H), 1.88-1.84 (m, 2H), 1.60-1.53 (m, 2H). SC_3397 cis-8-Dimethylamino-3-[2-[(2- INT-976 2-{[6-bromo-1-(2-trimethylsilanyl- SC_3242 (for step 1), 1HNMR (DMSO-d6, 400 MHz at 100° C.), δ 463.3 hydroxy-ethyl)-methyl-amino]-1H- ethoxymethyl)-1H-benzoimidazol-2-yl]- step 2 of SC_3352 (for step 2) (ppm) = 10.62 (bs, 1H), 7.48-7.24 (m, 6H), benzoimidazol-5-yl]-8-phenyl-1,3- methyl-amino}-ethanol (step 1) 7.01-6.91 (m, 2H,), 6.76 (s, 1H), 4.58 (bs, diazaspiro[4.5]decan-2-one 1H), 3.66 (t, 2H, J = 5.62 Hz), 3.54-3.50 (m, 4H), 3.09 (s, 3H), 2.37-2.32 (m, 2H), 2.04 (s, 6H), 1.96-1.91 (m, 4H), 1.52-1.40 (m, 2H). SC_3398 cis-8-Dimethylamino-3-(5-methyl- INT-976 4-(5-bromo-3-methyl- SC_3103 1H NMR (600 MHz, DMSO) δ 8.23 (s, 1H), 450.3 6-morpholin-4-yl-pyridin-3-yl)-8- 2-pyridyl)morpholine 7.83 (s, 1H), 7.46-7.33 (m, 5H), 7.30- phenyl-1,3-diazaspiro[4.5]decan-2- 7.24 (m, 1H), 3.71 (t, 4H), 3.55 (s, 2H), 2.93 one (t, 4H), 2.41-2.37 (m, 2H), 1.96 (s, 6H), 1.91-1.82 (m, 4H), 1.49-1.44 (m, 2H). SC_3399 cis-1-(Cyclopropyl-methyl)-8- SC_3409 bromomethylcyclopropane SC_3105 1HNMR (DMSO-d6, 400 MHz), δ (ppm) = 501.4 dimethylamino-8-(3-fluorophenyl)- 8.68-8.68 (d, 1H, J = 2.32 Hz), 8.42-8.40 (d, 3-(5-methylsulfonyl-pyridin-2-yl)- 1H, J = 9.04 Hz), 8.18-8.15 (m, 1H), 7.44- 1,3-diazaspiro[4.5]decan-2-one 7.38 (m, 1H), 7.20-7.08 (m, 3H), 3.90 (s, 2H), 3.22 (s, 3H), 3.11-3.10 (d, 2H, J = 6.68 Hz), 2.71-2.68 (d, 2H, J = 13.6 Hz), 2.27- 2.21(m, 2H), 2.00 (s, 6H), 1.53-1.44 (m, 4H), 1.02-0.99 (m, 1H), 0.54-0.50 (m, 2H), 0.36-0.35 (m, 2H). SC_3400 cis-1-(Cyclopropyl-methyl)-8-(3- SC_3399 SC_3099 1HNMR (DMSO-d6, 400 MHz), δ (ppm) = 487.2 fluorophenyl)-8-methylamino-3-(5- 8.72-8.71 (d, 1H, J = 2.28 Hz), 8.42-8.40 (d, methylsulfonyl-pyridin-2-yl)-1,3- 1H, J = 9.04 Hz), 8.18-8.15 (m, 1H), 7.40- diazaspiro[4.5]decan-2-one 7.31 (m, 3H), 7.05-7.01 (m, 1H), 3.93 (s, 2H), 3.23 (s, 3H), 3.14-3.13 (d, 2H, J = 6.76 Hz), 2.42 (bs, 1H), 2.28-2.23(m, 2H), 1.96- 1.88 (m, 5H), 1.79-1.73 (m, 2H), 1.44-1.41 (d, 2H, J = 12.2 Hz), 1.06-1.02 (m, 1H), 0.52-0.47 (m, 2H), 0.36-0.33 (m, 2H). SC_3401 cis-1-(Cyclobutyl-methyl)-8-(3- SC_3404 bromomethylcyclobutane (step 1) SC_3105 (for step 1), 1HNMR at 100° C. (DMSO-d6, 400 MHz), δ 492.1 fluorophenyl)-8-methylamino-3-[2- SC_3099 (for step 2) (ppm) = 9.23 (s, 2H), 7.38-7.26 (m, 3H), (trifluoromethyl)-pyrimidin-5-yl]- 7.00 (t, 1H, J = 8.1 Hz), 3.86 (s, 2H), 3.30- 1,3-diazaspiro[4.5]decan-2-one 3.28 (d, 2H, J = 7.24 Hz), 2.68-2.65 (m, 1H), 2.27-2.16 (m, 3H), 2.06-1.78 (m, 13H), 1.46- 1.43 (m, 2H). SC_3402 cis-1-(Cyclopropyl-methyl)-8- SC_3404 bromomethylcyclopropane SC_3105 1HNMR (DMSO-d6, 400 MHz), δ (ppm) = 492.0 dimethylamino-8-(3-fluorophenyl)- 9.21 (s, 2H), 7.45-7.39 (m, 1H), 7.22-7.18 3-[2-(trifluoromethyl)-pyrimidin-5- (m, 2H), 7.14-7.09 (m, 1H), 3.84 (s, 2H), yl]-1,3-diazaspiro[4.5]decan-2-one 3.09 (d, 2H, J = 6.4 Hz), 2.70 (d, 2H, J = 9.6 Hz), 2.32-2.21 (m, 2H), 2.01 (s, 6H), 1.59- 1.46 (m, 4H), 1.01-1.00 (m, 1H), 0.54-0.49 (m, 2H), 0.35-0.33 (m, 2H). SC_3403 cis-1-(Cyclopropyl-methyl)-8-(3- SC_3402 SC_3099 1HNMR (DMSO-d6, 400 MHz), δ (ppm) = 478.4 fluorophenyl)-8-methylamino-3-[2- 9.25 (s, 2H), 7.41-7.30 (m, 3H), 7.04 (t, 1H, (trifluoromethyl)-pyrimidin-5-yl]- J = 6.8 Hz), 3.89 (s, 2H), 3.12 (d, 2H, J = 6.8 1,3-diazaspiro[4.5]decan-2-one Hz), 2.41 (bs, 1H), 2.27-2.22 (m, 2H), 1.93- 1.78 (m, 7H), 1.46-1.43 (m, 2H), 1.08-1.03 (m, 1H), 0.51-0.47 (m, 2H), 0.33-0.29 (m, 2H). SC_3404 cis-8-Dimethylamino-8-(3- INT-1024 2-trifluoromethyl-5- SC_3242 1HNMR at 100° C. (DMSO-d6, 400 MHz), δ 437.9 fluorophenyl)-3-[2- bromopyrimidine (ppm) = 9.15 (s, 2H), 7.75 (s, 1H), 7.44-7.38 (trifluoromethyl)-pyrimidin-5-yl]- (m, 1H), 7.21-7.04 (m, 3H), 3.73 (s, 2H), 1,3-diazaspiro[4.5]decan-2-one 2.38-2.37 (m, 2H), 2.05 (s, 6H), 2.01-1.85 (m, 4H), 1.57-1.53 (m, 2H). SC_3405 cis-1-(Cyclopropyl-methyl)-8- SC_3319 bromomethylcyclopropane SC_3105 1HNMR at 100° C. (DMSO-d6, 400 MHz), δ 494.3 dimethylamino-8-(3-fluorophenyl)- (ppm) = 7.39-7.36 (m, 1H), 7.19-7.05 (m, 3-[2-methyl-5-(trifluoromethyl)- 3H), 6.56 (s, 1H), 3.78-3.67 (m, 5H), 3.10- 2H-pyrazol-3-yl]-1,3- 3.08 (d, 2H, J = 6.12 Hz), 2.64-2.60 (d, 2H, diazaspiro[4.5]decan-2-one J = 13.32 Hz), 2.37-2.26(m, 2H), 2.09 (s, 6H), 1.61-1.49 (m, 4H), 1.10-1.02 (m, 1H), 0.54- 0.52 (m, 2H), 0.36-0.33 (m, 2H). SC_3406 cis-1-(Cyclopropyl-methyl)-8-(3- SC_3405 SC_3099 1HNMR at 100° C. (DMSO-d6, 400 MHz), δ 480.0 fluorophenyl)-8-methylamino-3-[2- (ppm) = 7.39-7.24 (m, 3H), 6.99-6.96 (m, methyl-5-(trifluoromethyl)-2H- 1H), 6.58 (s, 1H), 3.78-3.71 (m, 5H), 3.11- pyrazol-3-yl]-1,3- 3.10 (d, 2H, J = 5.40 Hz), 2.30-2.23(m, 2H), diazaspiro[4.5]decan-2-one 1.99-1.92 (m, 5H), 1.79-1.72 (m, 2H), 1.58- 1.56 (m, 2H), 1.10-1.00 (m, 1H), 0.54-0.52 (m, 2H), 0.36-0.33 (m, 2H). SC_3407 cis-8-Methylamino-3-(4-methyl-2- SC_3148 SC_3099 437.3 morpholin-4-yl-pyrimidin-5-yl)-8- phenyl-1,3-diazaspiro[4.5]decan-2- one SC_3408 cis-3-[5-(Azetidin-1-yl)-3-methyl- INT-1024 5-(azetidin-1-yl)-2-chloro-3-methyl- SC_3103 1H NMR (600 MHz, DMSO) δ 7.44-7.36 438.3 pyridin-2-yl]-8-dimethylamino-8- pyridine (m, 2H), 7.20-7.05 (m, 4H), 6.69 (d, 1H), (3-fluorophenyl)-1,3- 3.82 (t, 4H), 3.51 (s, 2H), 2.36-2.26 (m, diazaspiro[4.5]decan-2-one 4H), 2.15 (s, 3H), 1.96 (s, 6H), 1.94-1.76 (m, 4H), 1.49 (t, 2H). SC_3409 cis-8-Dimethylamino-8-(3- INT-1024 2-bromo-5-methylsulfonyl- SC_3103 1H NMR (600 MHz, DMSO) δ 8.67 (dd, 447.2 fluorophenyl)-3-(5-methylsulfonyl- pyridine 1H), 8.39 (dd, 1H), 8.14 (dd, 1H), 8.04 (s, pyridin-2-yl)-1,3- 1H), 7.42 (td, 1H), 7.19 (d, 1H), 7.15 (dt, diazaspiro[4.5]decan-2-one 1H), 7.11 (td, 1H), 3.78 (s, 2H), 3.21 (s, 3H), 2.41-2.37 (m, 2H), 1.97 (s, 6H), 1.94- 1.75 (m, 4H), 1.54-1.45 (m, 2H). SC_3410 cis-3-(6-(azetidin--yl)-4- INT-976 2-(azetidin-1-yl)-5-bromo-4- SC_3103 fluoropyridin-3-yl)-8- fluoropyridine (dimethylamino)-8-phenyl-1,3- diazaspiro[4.5]decan-2-one SC_3411 cis-3-(6-(azetidin-1-yl)pyridin-3- INT-1024 2-(azetidin-1-yl)-5- SC_3103 yl)-8-(dimethylamino)-8-(3- bromopyridine fluorophenyl)-1,3- diazaspiro[4.5]decan-2-one SC_3412 cis-3-(1-(cyclopropanecarbonyl)-3- INT-1024 (5-bromo-3-(trifluoromethyl)-1H- SC_3103 (trifluoromethyl)-1H-pyrazol-5-yl)- pyrazol-1-yl)(cyclopropyl)methanone 8-(dimethylamino)-8-(3- fluorophenyl)-1,3- diazaspiro[4.5]decan-2-one SC_3413 cis-8-(dimethylamino)-8-(3- INT-1024 2-(5-bromo-3-(trifluoromethyl)-1H- SC_3242 fluorophenyl)-3-(1-(2- pyrazol-1-yl)ethanol hydroxyethyl)-3-(trifluoromethyl)- 1H-pyrazol-5-yl)-1,3- diazaspiro[4.5]decan-2-one SC_3414 cis-3-(1-(cyclopropylmethyl)-3- INT-1024 5-bromo-1-(cyclopropylmethyl)- SC_3242 480.2 (trifluoromethyl)-1H-pyrazol-5-yl)- 3-(trifluoromethyl)-1H-pyrazole 8-(dimethylamino)-8-(3- fluorophenyl)-1,3- diazaspiro[4.5]decan-2-one SC_3415 cis-8-(dimethylamino)-8-(3- INT-1024 5-bromo-1-(methylsulfonyl)-3- SC_3242 fluorophenyl)-3-(1- (trifluoromethyl)-1H-pyrazole (methylsulfonyl)-3- (trifluoromethyl)-1H-pyrazol-5-yl)- 1,3-diazaspiro[4.5]decan-2-one SC_3416 cis-1-(cyclopropylmethyl)-8- SC_3415 bromomethylcyclopropane SC_3105 (dimethylamino)-8-(3- fluorophenyl)-3-(1- (methylsulfonyl)-3- (trifluoromethyl)-1H-pyrazol-5-yl)- 1,3-diazaspiro[4.5]decan-2-one SC_3417 cis-2-(5-(8-(dimethylamino)-8-(3- INT-1024 2-(5-bromo-3-(trifluoromethyl)-1H- SC_3242 fluorophenyl)-2-oxo-1,3- pyrazol-1-yl)-N,N-dimethylacetamide diazaspiro[4.5]decan-3-yl)-3- (trifluoromethyl)-1H-pyrazol-1-yl)- N,N-dimethylacetamide SC_3418 cis-2-(5-(1-(cyclopropylmethyl)-8- SC_3417 bromomethylcyclopropane SC_3105 (dimethylamino)-8-(3- fluorophenyl)-2-oxo-1,3- diazaspiro[4.5]decan-3-yl)-3- (trifluoromethyl)-1H-pyrazol-1-yl)- N,N-dimethylacetamide SC_3419 cis-8-(dimethylamino)-3-(1-methyl- INT-976 5-bromo-1-methyl-1H-pyrrolo[2,3- SC_3103 404.3 1H-pyrrolo[2,3-b]pyridin-5-yl)-8- b]pyridine phenyl-1,3-diazaspiro[4.5]decan-2- one SC_3420 cis-8-(dimethylamino)-3-(3-fluoro- INT-976 5-bromo-3-fluoro-1-((2- SC_3352 408.2 1H-pyrrolo[2,3-b]pyridin-5-yl)-8- (trimethylsilyl)ethoxy)methyl)- phenyl-1,3-diazaspiro[4.5]decan-2- 1H-pyrrolo[2,3-b]pyridine (step 1) one SC_3421 cis-8-(dimethylamino)-8-phenyl-3- INT-976 4-bromo-1-((2- SC_3352 390.2 (1H-pyrrolo[2,3-c]pyridin-4-yl)- (trimethylsilyl)ethoxy)methyl)- 1,3-diazaspiro[4.5]decan-2-one 1H-pyrrolo[2,3-c]pyridine SC_3422 cis-8-(dimethylamino)-8-phenyl-3- INT-989 4-(4,4,5,5-tetramethyl-1,3,2- SC_3354 430.2 (2-(pyridazin-4-yl)pyrimidin-5-yl)- dioxaborolan-2-yl)pyridazine 1,3-diazaspiro[4.5]decan-2-one SC_3423 cis-8-(dimethylamino)-3-(2-(2-oxo- INT-989 (2-oxo-1,2-dihydropyridin-4- SC_3354 445.2 1,2-dihydropyridin-4-yl)pyrimidin- yl)boronic acid 5-yl)-8-phenyl-1,3- diazaspiro[4.5]decan-2-one SC_3424 cis-8-(dimethylamino)-8-(3- INT-1024 3,5-dibromo-1-methyl-1H-pyrazole SC_3103 (for step 1), fluorophenyl)-3-(1-methyl-3- (step 1), thiophen-2-ylboronic acid SC_3354 (for step 2) (thiophen-2-yl)-1H-pyrazol-5-yl)- (step 2) 1,3-diazaspiro[4.5]decan-2-one SC_3425 cis-8-(dimethylamino)-8-(3- INT-1024 3,5-dibromo-1-methyl-1H-pyrazole SC_3103 (for step 1), fluorophenyl)-3-(1-methyl-3- (step 1), morpholine (step 2) SC_3103 (for step 2) morpholino-1H-pyrazol-5-yl)-1,3- diazaspiro[4.5]decan-2-one SC_3426 cis-8-(dimethylamino)-8-phenyl-1- INT-1068 2-trifluoromethyl-5- SC_3103 502.2 (2,2,2-trifluoroethyl)-3-(2- bromopyrimidine (trifluoromethyl)pyrimidin-5-yl)- 1,3-diazaspiro[4.5]decan-2-one SC_3427 cis-8-(dimethylamino)-8-phenyl-3- INT-1070 2-trifluoromethyl-5- SC_3103 (2-(trifluoromethyl)pyrimidin-5- bromopyrimidine yl)-1-(3,3,3-trifluoropropyl)-1,3- diazaspiro[4.5]decan-2-one SC_3428 cis-3-(4-methyl-6- SC_3122 SC_3099 (trifluoromethyl)pyridin-3-yl)-8- (methylamino)-8-phenyl-1,3- diazaspiro[4.5]decan-2-one SC_3429 cis-3-(1-methyl-3- SC_3200 SC_3099 (trifluoromethyl)-1H-pyrazol-5-yl)- 8-(methylamino)-8-phenyl-1,3- diazaspiro[4.5]decan-2-one SC_3430 cis-8-(dimethylamino)-8-(3- INT-1024 3-bromo-4- SC_3103 fluorophenyl)-3-(4- (methylsulfonyl)pyridine (methylsulfonyl)pyridin-3-yl)-1,3- diazaspiro[4.5]decan-2-one SC_3431 cis-8-(dimethylamino)-3-(1-ethyl- INT-1024 5-bromo-1-ethyl-3- SC_3242 3-(trifluoromethyl)-1H-pyrazol-5- (trifluoromethyl)-1H-pyrazole yl)-8-(3-fluorophenyl)-1,3- diazaspiro[4.5]decan-2-one SC_3432 cis-3-(1-cyclopropyl-3- INT-1024 5-bromo-1-cyclopropyl-3- SC_3242 (trifluoromethyl)-1H-pyrazol-5-yl)- (trifluoromethyl)-1H-pyrazole 8-(dimethylamino)-8-(3- fluorophenyl)-1,3- diazaspiro[4.5]decan-2-one SC_3433 cis-8-(dimethylamino)-8-(3- INT-1024 5-bromo-1-(oxetan-3-ylmethyl)-3- SC_3242 fluorophenyl)-3-(1-(oxetan-3- (trifluoromethyl)-1H-pyrazole ylmethyl)-3-(trifluoromethyl)-1H- pyrazol-5-yl)-1,3- diazaspiro[4.5]decan-2-one SC_3434 cis-8-(dimethylamino)-8-(3- INT-1024 5-bromo-1-(2-(methylsulfonyl)ethyl)- SC_3242 fluorophenyl)-3-(1-(2- 3-(trifluoromethyl)-1H-pyrazole (methylsulfonyl)ethyl)-3- (trifluoromethyl)-1H-pyrazol-5-yl)- 1,3-diazaspiro[4.5]decan-2-one SC_3435 cis-8-(dimethylamino)-8-(3- INT-1076 methylamine SC_3239 fluorophenyl)-3-(4-methyl-2- (methylamino)pyrimidin-5-yl)-1,3- diazaspiro[4.5]decan-2-one SC_3436 cis-3-(2-cyclopropoxy-4- INT-1076 cyclopropanol SC_3224 440.3 methylpyrimidin-5-yl)-8- (dimethylamino)-8-(3- fluorophenyl)-1,3- diazaspiro[4.5]decan-2-one SC_3437 cis-N-(5-(8-(dimethylamino)-8-(3- INT-1024 N-(5-bromo-4-methylpyrimidin-2-yl)- SC_3103 481.3 fluorophenyl)-2-oxo-1,3- N-methylcyclopropanecarboxamide diazaspiro[4.5]decan-3-yl)-4- methylpyrimidin-2-yl)-N- methylcyclopropanecarboxamide SC_3438 cis-N-(5-(8-(dimethylamino)-8-(3- INT-1024 N-(5-bromo-4-methylpyrimidin-2-yl)- SC_3103 497.3 fluorophenyl)-2-oxo-1,3- N-methylpivalamide diazaspiro[4.5]decan-3-yl)-4- methylpyrimidin-2-yl)-N- methylpivalamide SC_3439 cis-3-(4-(azetidin-1-yl)-2- INT-1077 azetidine SC_3120 493.2 (trifluoromethyl)pyrimidin-5-yl)-8- (dimethylamino)-8-(3- fluorophenyl)-1,3- diazaspiro[4.5]decan-2-one SC_3440 cis-8-(dimethylamino)-8-(3- INT-1077 oxetan-3-ylmethanol SC_3224 524.2 fluorophenyl)-3-(4-(oxetan-3- ylmethoxy)-2- (trifluoromethyl)pyrimidin-5-yl)- 1,3-diazaspiro[4.5]decan-2-one SC_3441 cis-3-(2-cyclopropyl-4-(2,2,2- INT-1078 2,2,2-trifluoroethanol SC_3224 508.2 trifluoroethoxy)pyrimidin-5-yl)-8- (dimethylamino)-8-(3- fluorophenyl)-1,3- diazaspiro[4.5]decan-2-one SC_3442 cis-3-(2-cyclopropyl-4-((2-hy- INT-1078 2-(methylamino)ethanol SC_3120 483.3 droxyethyl)(methyl)amino)pyrimidin- 5-yl)-8-(dimethylamino)-8-(3- fluorophenyl)-1,3- diazaspiro[4.5]decan-2-one

Chemical Structures of all Examples

Pharmacological Investigations

Functional investigation on the human mu-opioid receptor (hMOP), human kappa-opioid receptor (hKOP), human delta-opioid receptor (hDOP), and human nociceptin/orphanin FQ peptide receptor (hNOP)

Human Mu-Opioid Peptide (hMOP) Receptor Binding Assay

The hMOP receptor binding assay was performed as homogeneous SPA-assay (scintillation proximity assay) using the assay buffer 50 mM TRIS-HCl (pH 7.4) supplemented with 0.052 mg/ml bovine serum albumin (Sigma-Aldrich Co. St. Louis. Mo.). The final assay volume (250 μl/well) included 1 nM of [N-allyl-2.3-³H]naloxone as ligand (PerkinElmer Life Sciences. Inc. Boston. Mass. USA). and either test compound in dilution series or 25 μM unlabeled naloxone for determination of unspecific binding. The test compound was diluted with 25% DMSO in H₂O to yield a final 0.5% DMSO concentration. which also served as a respective vehicle control. The assay was started by adding wheat germ agglutinin coated SPA beads (GE Healthcare UK Ltd. Buckinghamshire. UK) which had been preloaded with hMOP receptor membranes (PerkinElmer Life Sciences. Inc. Boston. Mass. USA). After incubation for 90 minutes at RT and centrifugation for 20 minutes at 500 rpm the signal rate was measured by means of a 1450 Microbeta Trilux ß-counter (PerkinElmer Life Sciences/Wallac. Turku. Finland). Half-maximal inhibitory concentration (TC50) values reflecting 50% displacement of [³H]naloxone-specific receptor binding were calculated by nonlinear regression analysis and Ki values were calculated by using the Cheng-Prusoff equation. (Cheng and Prusoff. 1973).

Human Kappa-Opioid Peptide (hKOP) Receptor Binding Assay

The hKOP receptor binding assay is run as homogeneous SPA-assay (scintillation proximity assay) using the assay buffer 50 mM TRIS-HCl (pH 7.4) supplemented with 0.076 mg BSA/ml. The final assay volume of 250 μl per well includes 2 nM of [³H]U69,593 as ligand, and either test compound in dilution series or 100 μM unlabeled naloxone for determination of unspecific binding. The test compound is diluted with 25% DMSO in H₂O to yield a final 0.5% DMSO concentration which serves as respective vehicle control, as well. The assays are started by the addition of wheat germ agglutinin coated SPA beads (1 mg SPA beads/250 μl final assay volume per well) which has been preloaded for 15 minutes at room temperature with hKOP receptor membranes (14.8 μg/250 μl final assay volume per well). After short mixing on a mini-shaker, the microtiter plates are covered with a lid and the assay plates are incubated for 90 minutes at room temperature. After this incubation, the microtiter plates are sealed with a topseal and centrifuged for 20 minutes at 500 rpm. The signal rate is measured after a short delay of 5 minutes by means of a 1450 Microbeta Trilux ß-counter (PerkinElmer Life Sciences/Wallac, Turku, Finland). Half-maximal inhibitory concentration (IC50) values reflecting 50% displacement of [³H]U69.593-specific receptor binding are calculated by nonlinear regression analysis and Ki values are calculated by using the Cheng-Prusoff equation, (Cheng and Prusoff, 1973).

Human Delta-Opioid Peptide (hDOP) Receptor Binding Assay

The hDOP receptor binding assay is performed as homogeneous SPA-assay using the assay buffer 50 mM TRIS-HCl, 5 mM MgCl₂ (pH 7.4). The final assay volume (250 μl/well) includes 1 nM of [Tyrosyl-3,5-³H]2-D-Ala-deltorphin II as ligand, and either test compound in dilution series or 10 μM unlabeled naloxone for determination of unspecific binding. The test compound is diluted with 25% DMSO in H₂O to yield a final 0.5% DMSO concentration which serves as respective vehicle control, as well. The assays are started by the addition of wheat germ agglutinin coated SPA beads (1 mg SPA beads/250 μl final assay volume per well) which has been preloaded for 15 minutes at room temperature with hDOP receptor membranes (15.2 μg/250 μl final assay volume per well). After short mixing on a mini-shaker, the microtiter plates are covered with a lid and the assay plates are incubated for 120 minutes at room temperature and centrifuged for 20 minutes at 500 rpm. The signal rate is measured by means of a 1450 Microbeta Trilux ß-counter (PerkinElmer Life Sciences/Wallac, Turku, Finland). Half-maximal inhibitory concentration (IC50) values reflecting 50% displacement of [Tyrosyl-3,5-³H]2-D-Ala-deltorphin II-specific receptor binding are calculated by nonlinear regression analysis and Ki values are calculated by using the Cheng-Prusoff equation, (Cheng and Prusoff, 1973).

Human Nociceptin/Orphanin FQ Peptide (hNOP) Receptor Binding Assay

The hNOP receptor binding assay was performed as homogeneous SPA-assay (scintillation proximity assay) using the assay buffer 50 mM TRIS-HCl. 10 mM MgCl₂. 1 mM EDTA (pH 7.4). The final assay volume (250 μl/well) included 0.5 nM of [leucyl-³H]nociceptin as ligand (PerkinElmer Life Sciences. Inc. Boston. Mass. USA). and either test compound in dilution series or 1 μM unlabeled nociceptin for determination of unspecific binding. The test compound was diluted with 25% DMSO in H₂O to yield a final 0.5% DMSO concentration. which also served as a respective vehicle control. The assay was started by adding wheat germ agglutinin coated SPA beads (GE Healthcare UK Ltd. Buckinghamshire. UK) which had been preloaded with hMOP receptor membranes (PerkinElmer Life Sciences. Inc. Boston. Mass. USA). After incubation for 60 minutes at RT and centrifugation for 20 minutes at 500 rpm the signal rate was measured by means of a 1450 Microbeta Trilux ß-counter (PerkinElmer Life Sciences/Wallac. Turku. Finland). Half-maximal inhibitory concentration (IC50) values reflecting 50% displacement of [³H]nociceptin-specific receptor binding were calculated by nonlinear regression analysis and Ki values were calculated by using the Cheng-Prusoff equation. (Cheng and Prusoff. 1973).

hNOP Ki [nM] hMOP Ki [nM] or % inhibition or % inhibition Example at 1 μM at 1 μM SC_3001 0.3 120 SC_3002 1.3 250 SC_3003 0.4 350 SC_3004 19.5 515 SC_3005 0.7 12 SC_3006 1.1 46 SC_3007 85.8 705 SC_3008 0.6 23 SC_3009 1.1 41 SC_3010 2.7 18 SC_3011 4.4 4.4 SC_3012 2.2 120 SC_3013 1.4 39 SC_3014 0.8 29.5 SC_3015 2.6 32.5 SC_3016 4.2 45 SC_3017 2 30 SC_3018 5.2 101.5 SC_3019 10.2 135 SC_3020 10.8 290 SC_3021 1.8 14.5 SC_3022 0.4 37.2 SC_3023 7.7 36 SC_3024 1 145 SC_3025 236.7 1530 SC_3026 4.6 300 SC_3027 5 136 SC_3028 0.6 10.4 SC_3029 1.8 7.3 SC_3030 2.2 59 SC_3031 4.1 45.5 SC_3032 11 245 SC_3033 107 38%@10 μM SC_3034 12.2 730 SC_3035 6.6 1055 SC_3036 1.4 220 SC_3037 33.5 775 SC_3038 1 76 SC_3039 13 380 SC_3040 4 335 SC_3041 0.9 79.5 SC_3042 4.1 136.5 SC_3043 70 655 SC_3044 230 10920 SC_3045 55.5 520 SC_3046 13.9 63 SC_3047 10.1 2105 SC_3048 1 38.5 SC_3049 25 940 SC_3050 85 28 SC_3051 3.6 170 SC_3052 160 355 SC_3053 73.5 1200 SC_3054 16.5 29.5 SC_3055 94.5 215 SC_3056 9.8 49.5 SC_3057 955 245 SC_3058 5 7.8 SC_3059 11.4 320 SC_3060 3 65 SC_3061 4.7 54.5 SC_3063 0.7 38 SC_3064 119 365 SC_3065 6.2 1990 SC_3066 2.2 96 SC_3067 41.5 99.5 SC_3068 5.9 50.5 SC_3069 2.6 49 SC_3070 2.8 12.5 SC_3071 8.2 170 SC_3072 5.9 235 SC_3073 1 110 SC_3074 1.6 55 SC_3075 8.1 260 SC_3076 0.6 35.3 SC_3077 3.2 325 SC_3078 0.6 77.5 SC_3079 1.6 38.5 SC_3080 1.6 90.5 SC_3081 8 1320 SC_3082 39 1110 SC_3083 12 117.3 SC_3084 1.8 22 SC_3085 1.6 107 SC_3086 1.1 43.5 SC_3087 2.8 99 SC_3088 3.1 770 SC_3089 3.3 235 SC_3090 1.3 67 SC_3091 2.3 24 SC_3092 2.2 330 SC_3093 1.1 47 SC_3094 5.4 45.5 SC_3096 14 250 SC_3097 17 18 SC_3098 2 6 SC_3099 13 19 SC_3100 1 1 SC_3101 1 3 SC_3102 2 1 SC_3103 7 1 SC_3104 — — SC_3105 2 97 SC_3106 8 165 SC_3107 2 115 SC_3108 5 26 SC_3109 8 19 SC_3110 6 20 SC_3111 8 37 SC_3112 36 120 SC_3113 24 26 SC_3114 245 460 SC_3115 265 915 SC_3116 6 170 SC_3117 92 1380 SC_3118 80  5% SC_3119 22%  10% SC_3120 26 4950 SC_3121 44 30% SC_3122 21 32% SC_3123 82 2260 SC_3124 5 1090 SC_3125 3%@10 μM 52%@10 μM SC_3126 0%  0% SC_3127 0% 3945 SC_3128 0%  1% SC_3129 6 2180 SC_3130 13 4530 SC_3131 4 3090 SC_3132 540  6% SC_3133 19 6515 SC_3134 3%@10 μM 40%@10 μM SC_3135 1%  1% SC_3136 16 5840 SC_3137 5 4235 SC_3138 28  7% SC_3139 59 1690 SC_3140 119 2355 SC_3141 34 7855 SC_3142 9 3750 SC_3143 0%  4% SC_3144 0% 3590 SC_3145 46 1635 SC_3146 18 7675 SC_3147 27 3325 SC_3148 14 4575 SC_3149 18 6900 SC_3150 105 16% SC_3151 115 3490 SC_3152 24 4775 SC_3153 77 2220 SC_3154 17 3575 SC_3155 34 3495 SC_3156 45 6375 SC_3157 35 5690 SC_3158 19 2540 SC_3159 13 19% SC_3160 4% 5730 SC_3161 2% 13% SC_3162 5 1325 SC_3163 28 2095 SC_3164 30 880 SC_3165 4% 17% SC_3166 3% 1640 SC_3167 18 3745 SC_3168 11 5 SC_3169 635 3445 SC_3170 7 3610 SC_3171 15 2010 SC_3172 130  7% SC_3173 10 2525 SC_3174 3% 1265 SC_3175 — — SC_3176 13 3740 SC_3177 8 4630 SC_3178 6 6700 SC_3179 15 3950 SC_3180 125 2250 SC_3181 22 5490 SC_3182 11 2990 SC_3183 165 1415 SC_3184 19 7645 SC_3185 335 15% SC_3186 33 2210 SC_3187 87 2240 SC_3188 25 1060 SC_3189 57 3470 SC_3190 42 28% SC_3191 27 20% SC_3192 140 4270 SC_3193 100 2480 SC_3194 28 5120 SC_3195 15 1240 SC_3196 22 1595 SC_3197 44 1680 SC_3198 22 5885 SC_3199 19 4020 SC_3200 7 13% SC_3201 115 3885 SC_3202 25 3210 SC_3203 68 1225 SC_3204 110 14% SC_3205 20 2465 SC_3206 27 2445 SC_3207 39 1505 SC_3208 2 3285 SC_3209 — — SC_3210 — — SC_3211 — — SC_3212 9 2005 SC_3213 52 18% SC_3214 7 19% SC_3215 0% 14% SC_3216 11 14 SC_3217 23 2155 SC_3218 83 15% SC_3219 0%  1% SC_3220 10%@10 μM 24%@10 μM SC_3221 33 1935 SC_3222 6 1910 SC_3223 155 6150 SC_3224 10 1695 SC_3225 13 2520 SC_3226 — — SC_3227 16 3785 SC_3228 67 3135 SC_3229 105 3625 SC_3230 145 2485 SC_3231 120 2420 SC_3232 15 3475 SC_3233 38 1390 SC_3234 4 1350 SC_3235 30 1095 SC_3236 285 18% SC_3237 20 17% SC_3238 4 25% SC_3239 35 2410 SC_3240 28 17% SC_3241 8 4610 SC_3242 5 675 SC_3243 6 695 SC_3244 27 4265 SC_3245 67 — SC_3246 11 1025 SC_3247 16 1220 SC_3248 4 41 SC_3249 740 855 SC_3250 52 — SC_3251 185 4550 SC_3252 30 — SC_3253 205 — SC_3254 22 240 SC_3255 23 150 SC_3256 12 61 SC_3257 150 240 SC_3258 58 7125 SC_3259 45 180 SC_3260 570 nd SC_3261 10 63 SC_3262 540 3060 SC_3263 66 800 SC_3264 145 130 SC_3265 38 2405 SC_3266 245 1055 SC_3267 460 — SC_3268 41 1625 SC_3269 13 5580 SC_3270 305 31 SC_3271 34 245 SC_3272 115 4175 SC_3273 — — SC_3274 63 1880 SC_3275 155 124 SC_3276 24 130 SC_3277 37 13% SC_3278 12 7035 SC_3279 17 78 SC_3280 6 300 SC_3281 19 2580 SC_3282 37 3510 SC_3283 12 1030 SC_3284 5 305 SC_3285 15 20% SC_3286 18 5895 SC_3287 119 18% SC_3288 15 115 SC_3289 84 430 SC_3290 16 6605 SC_3291 350 15% SC_3292 4%  0% SC_3293 3%  0% SC_3294 9 12% SC_3295 28 2975 SC_3296 10 4530 SC_3297 8 4270 SC_3298 20 17% SC_3299 23 5705 SC_3300 22 565 SC_3301 33 2320 SC_3302 31 1025 SC_3303 450 21% SC_3304 9%  4% SC_3305 10%   0% SC_3306 9 4555 SC_3307 13 5345 SC_3308 2 2575 SC_3309 17 6910 SC_3310 7 23% SC_3311 14 27% SC_3312 23 1830 SC_3313 10 2400 SC_3314 9 4090 SC_3315 14 5325 SC_3316 255 5430 SC_3317 56 6045 SC_3318 35 1235 SC_3319 4 15% SC_3320 11 1955 SC_3321 13 5715 SC_3322 12 1150 SC_3323 27 5530 SC_3324 12%   5% SC_3325 53%@10 μM 20%@10 μM SC_3326 — — SC_3327 17 3360 SC_3328 31 3295 SC_3329 13 4285 SC_3330 14 1505 SC_3331 2 5265 SC_3332 19 2055 SC_3333 5 1580 SC_3334 17 4005 SC_3335 30 2305 SC_3336 240 13% SC_3337 10 1970 SC_3338 36  7% SC_3339 10 6830 SC_3340 150 5750 SC_3341 15 3460 SC_3342 21 3845 SC_3343 27 16% SC_3344 1 13% SC_3345 4 1800 SC_3346 12 2580 SC_3347 15 4845 SC_3348 25 4090 SC_3349 8 3980 SC_3350 7 1485 SC_3351 20 2205 SC_3352 37 2160 SC_3353 53 15% SC_3354 2 23% SC_3355 52 4785 SC_3356 9 4805 SC_3357 13 555 SC_3358 51 7020 SC_3359 66 3520 SC_3360 7 2870 SC_3361 27 5095 SC_3362 28 29% SC_3363 33  8% SC_3364 32 4685 SC_3365 2 1655 SC_3366 1285 14% SC_3367 1220  8% SC_3368 195 11% SC_3369 51 3105 SC_3370 4 14% SC_3371 350  9% SC_3372 125 3535 SC_3373 19 18% SC_3374 55 10% SC_3375 13 12% SC_3376 37 1720 SC_3377 22 980 SC_3379 11 635 SC_3380 102 5415 SC_3381 3 1235 SC_3382 29 13% SC_3383 10 17% SC_3384 6 11% SC_3385 33 925 SC_3386 14  0% SC_3387 2 1245 SC_3388 29 185 SC_3389 2 1970 SC_3390 18 465 SC_3391 53 10% SC_3392 7 4490 SC_3393 88 13% SC_3394 6 735 SC_3395 14 4990 SC_3396 44 1730 SC_3397 48 560 SC_3398 9 5640 SC_3399 5 45% SC_3400 8 635 SC_3401 1 455 SC_3402 7 3630 SC_3403 9 1440 SC_3404 10  5% SC_3405 12 925 SC_3406 24 805 SC_3407 77 13% SC_3408 7 18% SC_3409 11 25%

Protocol for [³⁵S]GTPγS Functional NOP/MOP/KOP/DOP Assays

Cell membrane preparations of CHO-K1 cells transfected with the human MOP receptor (Art.-No. RBHOMM) or the human DOP receptor (Art.-No. RBHODM), and HEK293 cells transfected with the human NOP receptor (Art.-No. RBHORLM) or the human KOP receptor (Art.-No. 6110558) are available from PerkinElmer (Waltham, Mass.). Membranes from CHO-K1 cells transfected with the human nociceptin/orphanin FQ peptide (hNOP) receptor (Art.-No. 93-0264C2, DiscoveRx Corporation, Freemont, Calif.) are also used. [⁵S]GTPγS (Art.-No. NEG030H; Lot-No. #0112, #0913, #1113 calibrated to 46.25 TBq/mmol) is available from PerkinElmer (Waltham, Mass.).

The [³⁵S]GTPγS assays are carried out essentially as described by Gillen et al (2000). They are run as homogeneous scintillation proximity (SPA) assays in microtiter luminescence plates, where each well contains 1.5 mg of WGA-coated SPA-beads. To test the agonistic activity of test compounds on recombinant hNOP, hMOP, hDOP, and hKOP receptor expressing cell membranes from CHO-K1 or HEK293 cells, 10 or 5 μg membrane protein per assay are incubated with 0.4 nM [³⁵S]GTPγS and serial concentrations of receptor-specific agonists in buffer containing 20 mM HEPES pH 7.4, 100 mM NaCl, 10 mM MgCl2, 1 mM EDTA, 1 mM dithiothreitol, 1.28 mM NaN₃, and 10 μM GDP for 45 min at room temperature. The microtiter plates are then centrifuged for 10 min at 830 to sediment the SPA beads. The microtiter plates are sealed and the bound radioactivity [cpm] is determined after a delay of 15 min by means of a 1450 Microbeta Trilux (PerkinElmer, Waltham, Mass.).

The unstimulated basal binding activity (UBS_(obs) [cpm]) is determined from 12 unstimulated incubates and is set as 100% basal binding. For determination of the potency and the efficacy, the arithmetic mean of the observed total [³⁵S]GTPγS binding (TB_(obs) [cpm]) of all incubates (duplicates) stimulated by the receptor-specific agonists (i.e. N/OFQ, SNC80, DAMGO, or U69,593) are transformed in percent total binding (TB_(obs) [%]) relative to the basal binding activity (i.e. 100% binding). The potency (EC₅₀) of the respective agonist and its maximal achievable total [³⁵S]GTPγS binding (TB_(calc) [%]) above its calculated basal binding (UBS_(calc) [%]) are determined from its transformed data (TB_(obs) [%]) by means of nonlinear regression analysis with XLfit for each individual concentration series. Then the difference between the calculated unstimulated [³⁵S]GTPγS binding (UBS_(calc) [%]) and the maximal achievable total [³⁵S]GTPγS binding (TB_(calc) [%]) by each tested agonist is determined (i.e. B1_(calc) [%]). This difference (B1_(calc) [%]) as a measure of the maximal achievable enhancement of [³⁵S]GTPγS binding by a given agonist is used to calculate the relative efficacy of test compounds versus the maximal achievable enhancement by a receptor-specific full agonist, e.g. N/OFQ (B1_(calc-N/OFQ) [%]) which is set as 100% relative efficacy for the hNOP receptor. Likewise, the percentage efficacies of test compounds at the hDOP, hMOP, or hKOP receptor are determined versus the calculated maximal enhancement of [³⁵S]GTPγS binding by the full agonists SNC80 (B1_(calc-SNC80) [%]), DAMGO (B1_(calc-DAMGO) [%]) and U69,593 (B1_(calc-U69,593) [%]) which are set as 100% relative efficacy at each receptor, respectively.

The foregoing description and examples have been set forth merely to illustrate the invention and are not intended to be limiting. Since modifications of the described embodiments incorporating the spirit and substance of the invention may occur to persons skilled in the art, the invention should be construed broadly to include all variations within the scope of the appended claims and equivalents thereof. 

1. A compound according to general formula (I)

wherein R¹ and R² independently of one another mean —H; —C₁-C₆-alkyl, linear or branched, saturated or unsaturated, unsubstituted or substituted with one, two, three or four substituents independently of one another selected from the group consisting of —F, —Cl, —Br, —I, —OH, —OCH₃, —CN and —CO₂CH₃; a 3-12-membered cycloalkyl moiety, saturated or unsaturated, unsubstituted or substituted with one, two, three or four substituents independently of one another selected from the group consisting of —F, —Cl, —Br, —I, —OH, —OCH₃, —CN and —CO₂CH₃; wherein said 3-12-membered cycloalkyl moiety is optionally connected through —C₁-C₆-alkylene-, linear or branched, saturated or unsaturated, unsubstituted; or a 3-12-membered heterocycloalkyl moiety, saturated or unsaturated, unsubstituted or substituted with one, two, three or four substituents independently of one another selected from the group consisting of —F, —Cl, —Br, —I, —OH, —OCH₃, —CN and —CO₂CH₃; wherein said 3-12-membered heterocycloalkyl moiety is optionally connected through —C₁-C₆-alkylene-, linear or branched, saturated or unsaturated, unsubstituted; or R¹ and R² together with the nitrogen atom to which they are attached form a ring and mean —(CH₂)₃₋₆—; —(CH₂)₂—O—(CH₂)₂—; or —(CH₂)₂—NR^(A)—(CH₂)₂—, wherein R^(A) means —H or —C₁-C₆-alkyl, linear or branched, saturated or unsaturated, unsubstituted or substituted with one, two, three or four substituents independently of one another selected from the group consisting of —F, —Cl, —Br and —I; R³ means —C₁-C₆-alkyl, linear or branched, saturated or unsaturated, unsubstituted, mono- or polysubstituted; a 3-12-membered cycloalkyl moiety, saturated or unsaturated, unsubstituted, mono- or polysubstituted; wherein said 3-12-membered cycloalkyl moiety is optionally connected through —C₁-C₆-alkylene-, linear or branched, saturated or unsaturated, unsubstituted, mono- or polysubstituted; a 3-12-membered heterocycloalkyl moiety, saturated or unsaturated, unsubstituted, mono- or polysubstituted; wherein said 3-12-membered heterocycloalkyl moiety is optionally connected through —C₁-C₆-alkylene-, linear or branched, saturated or unsaturated, unsubstituted, mono- or polysubstituted; a 6-14-membered aryl moiety, unsubstituted, mono- or polysubstituted; wherein said 6-14-membered aryl moiety is optionally connected through —C₁-C₆-alkylene-, linear or branched, saturated or unsaturated, unsubstituted, mono- or polysubstituted; or a 5-14-membered heteroaryl moiety, unsubstituted, mono- or polysubstituted; wherein said 5-14-membered heteroaryl moiety is optionally connected through —C₁-C₆-alkylene-, linear or branched, saturated or unsaturated, unsubstituted, mono- or polysubstituted; R⁴ means —H; —C₁-C₆-alkyl, linear or branched, saturated or unsaturated, unsubstituted, mono- or polysubstituted; wherein said —C₁-C₆-alkyl is optionally connected through —C(═O)—, —C(═O)O—, or —S(═O)₂—; a 3-12-membered cycloalkyl moiety, saturated or unsaturated, unsubstituted, mono- or polysubstituted; wherein said 3-12-membered cycloalkyl moiety is optionally connected through —C₁-C₆-alkylene-, linear or branched, saturated or unsaturated, unsubstituted, mono- or polysubstituted; or wherein said 3-12-membered cycloalkyl moiety is optionally connected through —C(═O)—, —C(═O)O—, —C(═O)O—CH₂—, or —S(═O)₂—; a 3-12-membered heterocycloalkyl moiety, saturated or unsaturated, unsubstituted, mono- or polysubstituted; wherein said 3-12-membered heterocycloalkyl moiety is optionally connected through —C₁-C₆-alkylene-, linear or branched, saturated or unsaturated, unsubstituted, mono- or polysubstituted; or wherein said 3-12-membered heterocycloalkyl moiety is optionally connected through —C(═O)—, —C(═O)O—, —C(═O)O—CH₂—, or —S(═O)₂—; a 6-14-membered aryl moiety, unsubstituted, mono- or polysubstituted; wherein said 6-14-membered aryl moiety is optionally connected through —C₁-C₆-alkylene-, linear or branched, saturated or unsaturated, unsubstituted, mono- or polysubstituted; or wherein said 6-14-membered aryl moiety is optionally connected through —C(═O)—, —C(═O)O—, —C(═O)O—CH₂—, or —S(═O)₂—; or a 5-14-membered heteroaryl moiety, unsubstituted, mono- or polysubstituted; wherein said 5-14-membered heteroaryl moiety is optionally connected through —C₁-C₆-alkylene-, linear or branched, saturated or unsaturated, unsubstituted, mono- or polysubstituted; or wherein said 5-14-membered heteroaryl moiety is optionally connected through —C(═O)—, —C(═O)O—, —C(═O)O—CH₂—, or —S(═O)₂—; R⁵ means a 6-14-membered aryl moiety, unsubstituted, mono- or polysubstituted; or a 5-14-membered heteroaryl moiety, unsubstituted, mono- or polysubstituted; R¹¹, R¹², R¹³, R¹⁴, R¹⁵, R¹⁶, R¹⁷, R¹⁸, R¹⁹, and R²⁰ independently of one another mean —H, —F, —Cl, —Br, —I, —OH, or —C₁-C₆-alkyl, linear or branched, saturated or unsaturated, unsubstituted, mono- or polysubstituted; wherein “mono- or polysubstituted” means that one or more hydrogen atoms are replaced by a substituent independently of one another selected from the group consisting of —F, —Cl, —Br, —I, —CN, —R, —C(═O)R²¹, —C(═O)OR²¹, —C(═O)NR²¹R²², —C(═O)NH—(CH₂CH₂—O)₁₋₃₀—CH₃, —O—(CH₂CH₂—O)₁₋₃₀—H, —O—(CH₂CH₂—O)₁₋₃₀—CH₃, ═O, —OR²¹, —OC(═O)R²¹, —OC(═O)OR²¹, —OC(═O)NR²¹R²², —NO₂, —NR²¹R²², —NR²¹—(CH₂)₁₋₆—C(═O)R²², —NR²¹—(CH₂)₁₋₆—C(═O)OR²², —NR²³—(CH₂)₁₋₆—C(═O)NR²¹R²², —NR²¹C(═O)R²², —NR²¹C(═O)—OR²², —NR²³C(═O)NR²¹R²², —NR²¹S(═O)₂R²², —SR²¹, —S(═O)R²¹, —S(═O)₂R²¹, —S(═O)₂OR², and —S(═O)₂NR²¹R²²; wherein R²¹, R²² and R²³ independently of one another mean —H; —C₁—C-alkyl, linear or branched, saturated or unsaturated, unsubstituted or substituted with one, two, three or four substituents independently of one another selected from the group consisting of —F, —Cl, —Br, —I, —CN, —OH, —NH₂, —CO₂H, —C(═O)O—C₁-C₆-alkyl, —C(═O)NH₂, —C(═O)NHC₁-C₆-alkyl, —C(═O)N(C₁-C₆-alkyl)₂, —O—C₁-C₆-alkyl and —S(═O)₂—C₁-C₆-alkyl; a 3-12-membered cycloalkyl moiety, saturated or unsaturated, unsubstituted, mono- or polysubstituted; wherein said 3-12-membered cycloalkyl moiety is optionally connected through —C₁-C₆-alkylene-, linear or branched, saturated or unsaturated, unsubstituted or substituted with one, two, three or four substituents independently of one another selected from the group consisting of —F, —Cl, —Br, —I, —CN, —OH, —NH₂, —C₁-C₆-alkyl and —O—C₁-C₆-alkyl; a 3-12-membered heterocycloalkyl moiety, saturated or unsaturated, unsubstituted, mono- or polysubstituted; wherein said 3-12-membered heterocycloalkyl moiety is optionally connected through —C₁-C₆-alkylene-, linear or branched, saturated or unsaturated, unsubstituted or substituted with one, two, three or four substituents independently of one another selected from the group consisting of —F, —Cl, —Br, —I, —CN, —OH, —NH₂, —C₁-C₆-alkyl and —O—C₁-C₆-alkyl; a 6-14-membered aryl moiety, unsubstituted, mono- or polysubstituted; wherein said 6-14-membered aryl moiety is optionally connected through —C₁-C₆-alkylene-, linear or branched, saturated or unsaturated, unsubstituted or substituted with one, two, three or four substituents independently of one another selected from the group consisting of —F, —Cl, —Br, —I, —CN, —OH, —NH₂, —C₁-C₆-alkyl and —O—C₁-C₆-alkyl; a 5-14-membered heteroaryl moiety, unsubstituted, mono- or polysubstituted; wherein said 5-14-membered heteroaryl moiety is optionally connected through —C₁-C₆-alkylene-, linear or branched, saturated or unsaturated, unsubstituted or substituted with one, two, three or four substituents independently of one another selected from the group consisting of —F, —Cl, —Br, —I, —CN, —OH, —NH₂, —C₁-C₆-alkyl and —O—C₁-C₆-alkyl; or R²¹ and R²² within —C(═O)NR²¹R²², —OC(═O)NR²¹R²², —NR²¹R²², —NR²³—(CH₂)₁₋₆—C(═O)NR²¹R²², —NR²³C(═O)NR²¹R²², or —S(═O)₂NR²¹R²² together with the nitrogen atom to which they are attached form a ring and mean —(CH₂)₃₋₆—; —(CH₂)₂—O—(CH₂)₂—; —(CH₂)₂— S(═O)₂—(CH₂)₂— or —(CH₂)₂—NR^(B)—(CH₂)₂—, wherein R^(B) means —H, —C₁-C₆-alkyl, —C(═O)—C₁-C₆-alkyl, or —S(═O)₂—C₁-C₆-alkyl, wherein said C₁-C₆-alkyl is linear or branched, saturated or unsaturated, unsubstituted or substituted with one, two, three or four substituents independently of one another selected from the group consisting of —F, —Cl, —Br, —I, —OH, —CO₂H, —C(═O)O—C₁-C₆-alkyl and —C(═O)NH₂; and wherein said ring is unsubstituted or substituted with one, two, three or four substituents independently of one another selected from the group consisting of —F, —Cl, —Br, —I, —CN, ═O, —OH, —NH₂, —C₁-C₆-alkyl and —O—C₁-C₆-alkyl; or a physiologically acceptable salt thereof.
 2. The compound according to claim 1, wherein R¹¹, R¹², R¹³, R¹⁴, R¹⁵, R¹⁶, R¹⁷, R¹⁸, R¹⁹, and R²⁰ independently of one another mean —H, —F, —OH, or —C₁-C₆-alkyl.
 3. The compound according to claim 1, wherein R¹ means —H; and R² means —C₁-C₆-alkyl, linear or branched, saturated or unsaturated, unsubstituted, mono- or polysubstituted.
 4. The compound according to claim 1, wherein R¹ means —CH₃; and R² means —C₁-C₆-alkyl, linear or branched, saturated or unsaturated, unsubstituted, mono- or polysubstituted.
 5. The compound according to claim 1, wherein R¹ means —H or —CH₃; and wherein R² means —CH₂-cycloalkyl, —CH₂-cyclobutyl, —CH₂-cyclopentyl, —CH₂-oxetanyl or —CH₂-tetrahydrofuranyl.
 6. The compound according to claim 1, wherein R¹ and R² together with the nitrogen atom to which they are attached form a ring and mean —(CH₂)₃₋₆—.
 7. The compound according to claim 1, wherein R³ means —C₁-C₆-alkyl, linear or branched, saturated or unsaturated, unsubstituted, mono- or polysubstituted.
 8. The compound according to claim 1, wherein R³ means a 6-14-membered aryl moiety, unsubstituted, mono- or polysubstituted.
 9. The compound according to claim 1, wherein R³ means a 5-14-membered heteroaryl moiety, unsubstituted, mono- or polysubstituted.
 10. The compound according to claim 1, wherein R⁴ means —H.
 11. The compound according to claim 1, wherein R⁴ means —C₁-C₆-alkyl, linear or branched, saturated or unsaturated, unsubstituted, mono- or polysubstituted.
 12. The compound according to claim 1, wherein R⁴ means a 3-12-membered cycloalkyl moiety, saturated or unsaturated, unsubstituted, mono- or polysubstituted; wherein the 3-12-membered cycloalkyl moiety is connected through —C₁-C₆-alkylene-, linear or branched, saturated or unsaturated, unsubstituted, mono- or polysubstituted.
 13. The compound according to claim 1, wherein R⁴ means a 3-12-membered heterocycloalkyl moiety, saturated or unsaturated, unsubstituted, mono- or polysubstituted; wherein said 3-12-membered heterocycloalkyl moiety is connected through —C₁-C₆-alkylene-, linear or branched, saturated or unsaturated, unsubstituted, mono- or polysubstituted.
 14. The compound according to claim 1, wherein R⁴ means a 6-14-membered aryl moiety, unsubstituted, mono- or polysubstituted; wherein said 6-14-membered aryl moiety is connected through —C₁-C₆-alkylene-, linear or branched, saturated or unsaturated, unsubstituted, mono- or polysubstituted.
 15. The compound according to claim 1, wherein R⁴ means a 5-14-membered heteroaryl moiety, unsubstituted, mono- or polysubstituted; wherein said 5-14-membered heteroaryl moiety is connected through —C₁-C₆-alkylene-, linear or branched, saturated or unsaturated, unsubstituted, mono- or polysubstituted.
 16. The compound according to claim 1, wherein R⁵ means -phenyl, unsubstituted, mono- or polysubstituted.
 17. The compound according to claim 1, wherein R⁵ means a monocyclic 5-6-membered heteroaryl moiety, unsubstituted, mono- or polysubstituted.
 18. The compound according to claim 1, wherein R⁵ means a bicyclic 9-10-membered heteroaryl moiety, unsubstituted, mono- or polysubstituted.
 19. The compound according to claim 17, wherein R⁵ means -1,2-benzodioxole, -pyrazinyl, -pyridazinyl, -pyridinyl, -pyrimidinyl, -thienyl, -imidazolyl, -benzimidazolyl, -thiazolyl, -1,3,4-thiadiazolyl, -benzothiazolyl, -oxazolyl, -benzoxazolyl, -pyrazolyl, -quinolinyl, -isoquinolinyl, -quinazolinyl, -indolyl, -indolinyl, -benzo[c][1,2,5]oxadiazolyl, -imidazo[1,2-a]pyrazinyl, or -1H-pyrrolo[2,3-b]pyridinyl, in each case unsubstituted, mono- or polysubstituted.
 20. The compound according to claim 1, which has a structure according to any of general formulas (II-A) to (VIII-C):

wherein in each case R¹, R², R³, R⁴, and R⁵ are defined as in any of the preceding claims, R^(C) means —H, —OH, —F, —CN or —C₁-C₄-alkyl; R^(D) means —H or —F; or a physiologically acceptable salt thereof.
 21. The compound according to claim 1, wherein R⁵ is selected from the group consisting of:


22. The compound according to claim 1, wherein R¹means —H or —CH₃; R² means —C₁-C₆-alkyl, linear or branched, saturated, unsubstituted; cyclopropyl connected through —CH₂—; or tetrahydropyranyl connected through —CH₂—; R³ means -phenyl, benzyl, -thienyl or -pyridinyl, in each case unsubstituted or substituted with one, two, three or four substituents independently of one another selected from the group consisting of —F, —Cl, —CN, —CH₃, —CH₂CH₃, —CH₂F, —CHF₂, —CF₃, —OCF₃, —OH, —OCH₃, —C(═O)NH₂, C(═O)NHCH₃, —C(═O)N(CH₃)₂, —NH₂, —NHCH₃, —N(CH₃)₂, —NHC(═O)CH₃, —CH₂OH, SOCH₃ and SO₂CH₃; or R⁴ means —H; —C₁-C₆-alkyl, linear or branched, saturated, unsubstituted or substituted with one, two, three or four substituents independently of one another selected from the group consisting of —F, —Cl, —Br, —I, —CN, —OH, —O—C₁-C₄-alkyl, —C(═O)NH—C₁-C₆-alkyl, —C(═O)N(C₁-C₆-alkyl)₂ or —C(═O)NRR′ wherein R and R′ together with the nitrogen atom to which they are attached form a ring and mean —(CH₂)₃₋₅—; 3-6-membered cycloalkyl, unsubstituted or substituted with one, two, three or four substituents independently of one another selected from the group consisting of —F, —Cl, —Br, —I, —CN, —OH, and —O—C₁-C₄-alkyl, wherein said 3-6-membered cycloalkyl is connected through —C₁-C₆-alkylene; 3-6-membered heterocycloalkyl, unsubstituted or substituted with one, two, three or four substituents independently of one another selected from the group consisting of —F, —Cl, —Br, —I, —CN, —OH, and —O—C₁-C₄-alkyl, wherein said 3-6-membered heterocycloalkyl is connected through —C₁-C₆-alkylene; phenyl, unsubstituted or monosubstituted with —OCH₃; wherein said -phenyl is connected through —C₁-C₆-alkylene-; or -pyridyl, unsubstituted, mono- or polysubstituted; wherein said -pyridyl is connected through —C₁-C₆-alkylene-; R⁵ means -phenyl, -1,2-benzodioxole, -pyrazinyl, -pyridazinyl, -pyridinyl, -pyrimidinyl, -thienyl, -imidazolyl, -benzimidazolyl, -thiazolyl, -1,3,4-thiadiazolyl, -benzothiazolyl, -oxazolyl, -benzoxazolyl, -pyrazolyl, -quinolinyl, -isoquinolinyl, -quinazolinyl, -indolyl, -indolinyl, -benzo[c][1,2,5]oxadiazolyl, -imidazo[1,2-a]pyrazinyl, or -1H-pyrrolo[2,3-b]pyridinyl, in each case unsubstituted or substituted with one, two, three or four substituents independently of one another selected from the group consisting of —F; —Cl; —Br; —I; —CN; —C₁-C₄-alkyl; —C₁-C₄-alkyl-OH; —CF₃; —C₁-C₄-alkyl-CF₃; —C₁-C₄-alkyl-C(═O)NH₂; —C₁-C₄-alkyl-C(═O)NHC₁-C₆-alkyl; —C₁-C₄-alkyl-C(═O)N(C₁-C₆-alkyl)₂; —C₁-C₄-alkyl-S(═O)₂—C₁-C₄-alkyl; —C(═O)—C₁-C₄-alkyl; —C(═O)OH; —C(═O)O—C₁-C₄-alkyl; —C(═O)NH₂; —C(═O)NHC₁-C₄-alkyl; —C(═O)N(C₁-C₄-alkyl)₂; —C(═O)NH(C₁-C₄-alkyl-OH); —C(═O)N(C₁-C₄-alkyl)(C₁-C₄-alkyl-OH); —C(═O)NH—(CH₂CH₂O)₁₋₃₀—CH₃; —NH₂; —NHC₁-C₄-alkyl; —N(C₁-C₄-alkyl)₂; —NHC₁-C₄-alkyl-OH; -NCH₃C₁-C₄-alkyl-OH; —NH—C₁-C₄-alkyl-C(═O)NH₂; —NCH₃—C₁-C₄-alkyl-C(═O)NH₂; —NHC(═O)—C₁-C₄-alkyl; —NCH₃C(═O)—C₁-C₄-alkyl; —OH; —O—C₁-C₄-alkyl; —OCF₃; —O—C₁-C₄-alkyl-CO₂H; —O—C₁-C₄-alkyl-C(═O)O—C₁-C₄-alkyl; —O—C₁-C₄-alkyl-CONH₂; —S—C₁-C₄-alkyl; —S(═O)C₁-C₄-alkyl; —S(═O)₂C₁-C₄-alkyl; and —S(═O)₂N(C₁-C₄-alkyl)₂; -3-12-membered cycloalkyl, saturated or unsaturated, unsubstituted, mono- or polysubstituted; wherein said 3-12-membered cycloalkyl is optionally connected through —CH₂—, —O—, —NH—, —NCH₃—, —NH—(CH₂)₁₋₃—, —NCH₃(CH₂)₁₋₃—, —(C═O)—, —NHC(═O)—, —NCH₃C(═O)—, —C(═O)NH—(CH₂)₁₋₃—, —C(═O)NCH₃—(CH₂)₁₋₃—; -3-12-membered heterocycloalkyl, saturated or unsaturated, unsubstituted, mono- or polysubstituted; wherein said 3-12-membered heterocycloalkyl is optionally connected through —CH₂—, —O—, —NH—, —NCH₃—, —NH—(CH₂)₁₋₃—, -NCH₃(CH₂)₁₋₃—, —(C═O)—, —NHC(═O)—, —NCH₃C(═O)—, —C(═O)NH—(CH₂)₁₋₃—, —C(═O)NCH₃—(CH₂)₁₋₃—; -6-14-membered aryl, unsubstituted, mono- or polysubstituted; wherein said 6-14-membered aryl is optionally connected through —CH₂—, —O—, —NH—, —NCH₃—, —NH—(CH₂)₁₋₃—, —NCH₃(CH₂)₁₋₃—, —(C═O)—, —NHC(═O)—, —NCH₃C(═O)—, —C(═O)NH—(CH₂)₁₋₃—, —C(═O)NCH₃—(CH₂)₁₋₃—; or -5-14-membered heteroaryl, unsubstituted, mono- or polysubstituted; wherein said 5-14-membered heteroaryl is optionally connected through —CH₂—, —O—, —NH—, —NCH₃—, —NH—(CH₂)₁₋₃—, —NCH₃(CH₂)₁₋₃—, —(C═O)—, —NHC(═O)—, —NCH₃C(═O)—, —C(═O)NH—(CH₂)₁₋₃—, —C(═O)NCH₃—(CH₂)₁₋₃—; and R¹¹, R¹², R¹³, R¹⁴, R¹⁵, R¹⁶, R¹⁷, R¹⁸, R¹⁹, and R²⁰ mean —H.
 23. The compound according to claim 1, which has a structure according to general formula (I′)

wherein R¹ to R⁵, R¹¹ to R²⁰ are defined as in claim 1, or a physiologically acceptable salt thereof.
 24. The compound according to claim 1, which has a structure according to general formula (IX) or (X)

wherein R² means —H or —CH₃; R³ means -phenyl or -3-fluorophenyl; R^(C) means —H or —OH; R^(E) means —H, —CH₃, —F, —CF₃, -cyclopropyl, -aziridinyl, —OH; —O—C₁-C₄-alkyl; —OCF₃; —O—C₁-C₄-alkyl-CO₂H; —O—C₁-C₄-alkyl-C(═O)O—C₁-C₄-alkyl; or —O—C₁-C₄-alkyl-CONH₂; R^(F) means —CF₃, -cyclopropyl, —S(═O)₂CH₃, —NH₂; —NHC₁-C₄-alkyl; —N(C₁-C₄-alkyl)₂; —NHC₁-C₄-alkyl-OH; —NCH₃C₁-C₄-alkyl-OH; -NH—C₁-C₄-alkyl-C(═O)NH₂; —NCH₃—C₁-C₄-alkyl-C(═O)NH₂; —NHC(═O)—C₁-C₄-alkyl; —NCH₃C(═O)—C₁-C₄-alkyl; -6-14-membered aryl, unsubstituted, mono- or polysubstituted; or -5-14-membered heteroaryl, unsubstituted, mono- or polysubstituted; U means ═CH— or ═N—; and V means ═CH— or ═N—; or a physiologically acceptable salt thereof
 25. The compound according to claim 1, which has a structure according to general formula (XI)

wherein R² means —H or —CH₃; R³ means -phenyl or -3-fluorophenyl; R^(H) means —CN; —C₁-C₄-alkyl; —CF₃; —C₁-C₄-alkyl-C(═O)NH₂; —C₁-C₄-alkyl-S(═O)₂—C₁-C₄-alkyl; —C(═O)—C₁-C₄-alkyl; —C(═O)OH; —C(═O)O—C₁-C₄-alkyl; —C(═O)NH₂; —C(═O)NHC₁-C₄-alkyl; —C(═O)N(C₁-C₄-alkyl)₂; —C(═O)NH(C₁-C₄-alkyl-OH); —C(═O)N(C₁-C₄-alkyl)(C₁-C₄-alkyl-OH); —C(═O)NH—(CH₂CH₂O)₁₋₃₀—CH₃; -3-12-membered cycloalkyl, saturated or unsaturated, unsubstituted, mono- or polysubstituted; wherein said 3-12-membered cycloalkyl is optionally connected through —CH₂—, —NH—, —NCH₃—, —NH—(CH₂)₁₋₃—, —NCH₃(CH₂)₁₋₃—, —(C═O)—, —NHC(═O)—, —NCH₃C(═O)—, —C(═O)NH—(CH₂)₁₋₃—, —C(═O)NCH₃—(CH₂)₁₋₃—; or -3-12-membered heterocycloalkyl, saturated or unsaturated, unsubstituted, mono- or polysubstituted; 6-14-membered aryl, unsubstituted, mono- or polysubstituted; wherein said 3-12-membered heterocycloalkyl is optionally connected through —CH₂—, —NH—, —NCH₃—, —NH—(CH₂)₁₋₃—, —NCH₃(CH₂)₁₋₃—, —(C═O)—, —NHC(═O)—, —NCH₃C(═O)—, —C(═O)NH—(CH₂)₁₋₃—, —C(═O)NCH₃—(CH₂)₁₋₃—; R^(G) means —CF₃, —S(═O)₂CH₃; —NH₂; -NHC₁-C₄-alkyl; -N(C₁-C₄-alkyl)₂; -NHC₁-C₄-alkyl-OH; -NCH₃C₁-C₄-alkyl-OH; —NH—C₁-C₄-alkyl-C(═O)NH₂; —NCH₃—C₁-C₄-alkyl-C(═O)NH₂; —NHC(═O)—C₁-C₄-alkyl; —NCH₃C(═O)—C₁-C₄-alkyl; -3-12-membered cycloalkyl, saturated or unsaturated, unsubstituted, mono- or polysubstituted; wherein said 3-12-membered cycloalkyl is optionally connected through —CH₂—, —NH—, —NCH₃—, —NH—(CH₂)₁₋₃—, —NCH₃(CH₂)₁₋₃—, —(C═O)—, —NHC(═O)—, —NCH₃C(═O)—, —C(═O)NH—(CH₂)₁₋₃—, —C(═O)NCH₃—(CH₂)₁₋₃—; or -3-12-membered heterocycloalkyl, saturated or unsaturated, unsubstituted, mono- or polysubstituted; 6-14-membered aryl, unsubstituted, mono- or polysubstituted; wherein said 3-12-membered heterocycloalkyl is optionally connected through —CH₂—, —NH—, —NCH₃—, —NH—(CH₂)₁₋₃—, —NCH₃(CH₂)₁₋₃—, —(C═O)—, —NHC(═O)—, —NCH₃C(═O)—, —C(═O)NH—(CH₂)₁₋₃—, —C(═O)NCH₃—(CH₂)₁₋₃—; or a physiologically acceptable salt thereof.
 26. The compound according to claim 1, which is selected from the group consisting of cis-5-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-pyrimidine-2-carbonitrile; cis-5-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-pyrazine-2-carbonitrile; cis-5-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-4-methoxy-pyrimidine-2-carbonitrile; cis-5-[8-Dimethylamino-1-(2-methoxy-ethyl)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-pyrimidine-2-carbonitrile; cis-5-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-pyrimidine-2-carboxylic acid amide; cis-5-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-2-methylsulfonyl-pyrimidine-4-carbonitrile; cis-5-[1-(2-Methoxy-ethyl)-8-methylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-pyrimidine-2-carbonitrile; cis-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-5-methylsulfonyl-benzonitrile; cis-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-benzamide; cis-3-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-benzamide; cis-5-[8-Dimethylamino-1-[(1-hydroxy-cyclobutyl)-methyl]-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-pyrimidine-2-carboxylic acid amide; cis-5-[1-(Cyclobutyl-methyl)-8-methylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-4-methoxy-pyrimidine-2-carbonitrile; cis-5-[8-Dimethylamino-1-[(1-hydroxy-cyclobutyl)-methyl]-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-pyrimidine-2-carbonitrile; cis-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-pyrimidine-5-carbonitrile; cis-8-Dimethylamino-1-[(1-hydroxy-cyclobutyl)-methyl]-3-(2-methoxy-pyrimidin-5-yl)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one; cis-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-pyrimidine-5-carboxylic acid amide; cis-4-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-methyl-benzamide; cis-5-(8-Dimethylamino-2-oxo-8-phenyl-1-propyl-1,3-diazaspiro[4.5]decan-3-yl)-pyrimidine-2-carbonitrile; cis-5-[8-Dimethylamino-1-(3-methoxy-propyl)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-pyrimidine-2-carbonitrile; cis-5-[1-(Cyclopropyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-pyrimidine-2-carbonitrile; cis-4-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-benzamide; cis-1-(Cyclobutyl-methyl)-8-dimethylamino-8-phenyl-3-[2-(trifluoromethyl)-pyrimidin-5-yl]-1,3-diazaspiro[4.5]decan-2-one; cis-8-Dimethylamino-1-[(1-hydroxy-cyclobutyl)-methyl]-3-(2-hydroxy-pyrimidin-5-yl)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one; cis-5-[8-Dimethylamino-1-(2-methyl-propyl)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-pyrimidine-2-carbonitrile; cis-5-[8-Dimethylamino-1-(2-hydroxy-ethyl)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-pyrimidine-2-carbonitrile; cis-5-[1-(Cyclobutyl-methyl)-8-methylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-4-methyl-pyridine-2-carbonitrile; cis-1-(Cyclobutyl-methyl)-3-(5-methoxy-pyrazin-2-yl)-8-methylamino-8-phenyl-1,3-diazaspiro[4.5]decan-2-one; cis-4-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N,N-dimethyl-benzamide; cis-4-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-ethyl-N-(2-hydroxy-ethyl)-benzamide; cis-2-[1-(Cyclobutyl-methyl)-8-methylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-5-methylsulfonyl-benzonitrile; cis-1-(Cyclobutyl-methyl)-8-methylamino-3-[2-methylsulfonyl-4-(trifluoromethyl)-phenyl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one; cis-4-[1-(Cyclobutyl-methyl)-8-methylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N,N-dimethyl-3-(trifluoromethyl)-benzenesulfonic acid amide; cis-4-[1-(Cyclobutyl-methyl)-8-(ethyl-methyl-amino)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-benzonitrile; cis-1-(Cyclobutyl-methyl)-8-(ethyl-methyl-amino)-8-phenyl-3-[2-(trifluoromethyl)-pyrimidin-5-yl]-1,3-diazaspiro[4.5]decan-2-one; cis-5-[1-(Cyclobutyl-methyl)-8-(ethyl-methyl-amino)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-pyrimidine-2-carbonitrile; cis-5-[8-Dimethylamino-1-[(1-methyl-cyclobutyl)-methyl]-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-pyrimidine-2-carbonitrile; cis-2-[3-(2-Cyano-pyrimidin-5-yl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-1-yl]-N,N-dimethyl-acetamide; cis-1-(Cyclobutyl-methyl)-8-methylamino-8-phenyl-3-[2-(trifluoromethyl)-pyrimidin-5-yl]-1,3-diazaspiro[4.5]decan-2-one; cis-5-[8-Dimethylamino-8-(3-fluorophenyl)-1-(4-methoxy-butyl)-2-oxo-1,3-diazaspiro[4.5]decan-3-yl]-pyrimidine-2-carbonitrile; cis-5-[8-Dimethylamino-1-(3-methoxy-propyl)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-4-methoxy-pyrimidine-2-carbonitrile; cis-5-[1-[(1-Cyano-cyclobutyl)-methyl]-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-pyrimidine-2-carbonitrile; cis-N-(Cyclobutyl-methyl)-5-[1-(cyclobutyl-methyl)-8-dimethylamino-8-(3-fluorophenyl)-2-oxo-1,3-diazaspiro[4.5]decan-3-yl]-pyrimidine-2-carboxylic acid amide; cis-5-[1-(3-Methoxy-propyl)-8-methylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-pyrimidine-2-carbonitrile; cis-5-[8-Dimethylamino-8-(3-fluorophenyl)-1-methyl-2-oxo-1,3-diazaspiro[4.5]decan-3-yl]-pyrimidine-2-carbonitrile; cis-4-Methoxy-5-[1-(3-methoxy-propyl)-8-methylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-pyrimidine-2-carbonitrile; cis-4-[8-Dimethylamino-1-(2-methoxy-ethyl)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-pyrimidine-2-carbonitrile; cis-5-[8-Dimethylamino-1-(2-methoxy-ethyl)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-4-methoxy-pyrimidine-2-carbonitrile; cis-4-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-pyrimidine-2-carbonitrile; cis-1-(Cyclobutyl-methyl)-8-dimethylamino-3-(6-methylsulfanyl-pyrimidin-4-yl)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one; cis-2-[3-(2-Cyano-pyrimidin-4-yl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-1-yl]-N,N-dimethyl-acetamide; cis-6-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-pyrimidine-4-carbonitrile; cis-2-(8-Dimethylamino-2-oxo-3,8-diphenyl-1,3-diazaspiro[4.5]decan-1-yl)-N,N-dimethyl-acetamide; cis-1-(Cyclobutyl-methyl)-8-dimethylamino-3,8-diphenyl-1,3-diazaspiro[4.5]decan-2-one; cis-2-[8-Dimethylamino-1-(2-methoxy-ethyl)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-pyrimidine-5-carbonitrile; cis-8-Dimethylamino-1-(2-methoxy-ethyl)-3,8-diphenyl-1,3-diazaspiro[4.5]decan-2-one; cis-5-[8-Dimethylamino-1-(2-methoxy-ethyl)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-4-methyl-pyridine-2-carbonitrile; cis-N,N-Dimethyl-2-(8-methylamino-2-oxo-3,8-diphenyl-1,3-diazaspiro[4.5]decan-1-yl)-acetamide; cis-5-[1-[(1-Cyano-cyclobutyl)-methyl]-8-methylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-pyrimidine-2-carbonitrile; cis-5-[1-[(1-Cyano-cyclobutyl)-methyl]-8-(ethyl-methyl-amino)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-pyrimidine-2-carbonitrile; CIS-4-[8-Dimethylamino-1-[(1-hydroxy-cyclobutyl)-methyl]-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-benzonitrile; cis-3-[8-Dimethylamino-1-[(1-hydroxy-cyclobutyl)-methyl]-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-benzonitrile; cis-5-[1-[(1-Cyano-cyclobutyl)-methyl]-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-pyridine-2-carbonitrile; cis-2-[3-(2-Cyano-pyrimidin-5-yl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-1-yl]-N-propyl-acetamide; cis-5-[1-(Cyclobutyl-methyl)-8-(ethyl-methyl-amino)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-4-methoxy-pyrimidine-2-carbonitrile; cis-4-[1-(Cyclobutyl-methyl)-8-methylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-3-methoxy-benzonitrile; cis-5-[8-Dimethylamino-1-(3-methoxy-propyl)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-6-methoxy-pyridine-2-carbonitrile; cis-4-[8-Dimethylamino-1-[(1-hydroxy-cyclobutyl)-methyl]-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-benzamide; cis-5-[8-Dimethylamino-1-[(1-hydroxy-cyclobutyl)-methyl]-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-pyridine-2-carbonitrile; cis-5-[8-Dimethylamino-1-[(1-hydroxy-cyclobutyl)-methyl]-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-[(1-hydroxy-cyclobutyl)-methyl]-pyridine-2-carboxylic acid amide; cis-2-[8-Dimethylamino-1-[(1-hydroxy-cyclobutyl)-methyl]-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-benzonitrile; cis-3-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-benzonitrile; cis-1-(Cyclobutyl-methyl)-8-dimethylamino-8-phenyl-3-[2-(trifluoromethyl)-pyrimidin-5-yl]-1,3-diazaspiro[4.5]decan-2-one; cis-5-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-4-methyl-pyridine-2-carboxylic acid methyl ester; cis-1-(Cyclobutyl-methyl)-8-dimethylamino-3-(5-methoxy-pyrazin-2-yl)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one; cis-1-(Cyclobutyl-methyl)-8-dimethylamino-3-(2-methoxy-pyrimidin-5-yl)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one; cis-4-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-benzonitrile; cis-5-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-4-methyl-pyridine-2-carbonitrile; cis-1-(Cyclobutyl-methyl)-8-dimethylamino-3-(5-fluoro-pyrimidin-2-yl)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one; cis-4-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-3-methoxy-benzonitrile; cis-4-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-benzoic acid methyl ester; cis-1-(Cyclobutyl-methyl)-8-dimethylamino-8-phenyl-3-(2-pyrrolidin-1-yl-pyrimidin-4-yl)-1,3-diazaspiro[4.5]decan-2-one; cis-1-(Cyclobutyl-methyl)-8-dimethylamino-8-phenyl-3-(5-pyridin-2-yl-thiophen-2-yl)-1,3-diazaspiro[4.5]decan-2-one; cis-1-(Cyclobutyl-methyl)-8-dimethylamino-3-[2-methylsulfonyl-4-(trifluoromethyl)-phenyl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one; cis-1-(Cyclobutyl-methyl)-8-dimethylamino-8-phenyl-3-[6-(trifluoromethyl)-pyridin-3-yl]-1,3-diazaspiro[4.5]decan-2-one; cis-1-(Cyclobutyl-methyl)-3-(2,4-dimethoxy-phenyl)-8-dimethylamino-8-phenyl-1,3-diazaspiro[4.5]decan-2-one; cis-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-4-methylsulfonyl-benzonitrile; cis-5-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-2-fluoro-benzonitrile; cis-4-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N,N-dimethyl-3-(trifluoromethyl)-benzenesulfonic acid amide; cis-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-benzonitrile; cis-1-(Cyclobutyl-methyl)-8-dimethylamino-3-(2-methyl-imidazo[1,2-a]pyrazin-6-yl)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one; cis-1-(Cyclobutyl-methyl)-8-dimethylamino-3-(4-methylsulfonyl-phenyl)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one; cis-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-5-methoxy-benzonitrile; cis-1-(Cyclobutyl-methyl)-8-dimethylamino-3,8-diphenyl-1,3-diazaspiro[4.5]decan-2-one; cis-1-(Cyclobutyl-methyl)-8-dimethylamino-8-phenyl-3-pyrazin-2-yl-1,3-diazaspiro[4.5]decan-2-one; cis-8-Dimethylamino-1-[(1-hydroxy-cyclobutyl)-methyl]-3-(2-morpholin-4-yl-pyrimidin-5-yl)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one; cis-8-Dimethylamino-1-[(1-hydroxy-cyclobutyl)-methyl]-3-[2-(4-methyl-piperazin-1-yl)-pyrimidin-5-yl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one; cis-1-[(1-Hydroxy-cyclobutyl)-methyl]-8-methylamino-3-(2-morpholin-4-yl-pyrimidin-5-yl)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one; cis-8-Dimethylamino-1-[(1-hydroxy-cyclobutyl)-methyl]-8-phenyl-3-(2-piperazin-1-yl-pyrimidin-5-yl)-1,3-diazaspiro[4.5]decan-2-one hydrochloride; cis-1-[(1-Hydroxy-cyclobutyl)-methyl]-8-methylamino-3-[2-(4-methyl-piperazin-1-yl)-pyrimidin-5-yl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one; cis-1-[(1-Hydroxy-cyclobutyl)-methyl]-8-methylamino-8-phenyl-3-(2-piperazin-1-yl-pyrimidin-5-yl)-1,3-diazaspiro[4.5]decan-2-one dihydrochloride; cis-1-(Cyclobutyl-methyl)-8-dimethylamino-3-[4-methyl-6-(trifluoromethyl)-pyridin-3-yl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one; cis-1-(Cyclobutyl-methyl)-8-methylamino-3-[4-methyl-6-(trifluoromethyl)-pyridin-3-yl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one; cis-1-(Cyclopropyl-methyl)-8-dimethylamino-3-(4-methylsulfonyl-phenyl)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one; cis-1-(Cyclopropyl-methyl)-8-methylamino-3-(4-methylsulfonyl-phenyl)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one; cis-1-(Cyclopropyl-methyl)-8-dimethylamino-3-(2-fluoro-4-methylsulfonyl-phenyl)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one; cis-2-[8-Dimethylamino-1-[(1-hydroxy-cyclobutyl)-methyl]-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-benzamide; formic acid; cis-2-[8-Dimethylamino-1-[2-(1-methoxy-cyclobutyl)-ethyl]-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-benzamide; cis-8-Dimethylamino-1-[2-(1-methoxy-cyclobutyl)-ethyl]-3-(2-methyl-pyrimidin-5-yl)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one; cis-5-[1-[(1-Hydroxy-cyclobutyl)-methyl]-8-methylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-pyrimidine-2-carbonitrile; cis-2-[1-[(1-Hydroxy-cyclobutyl)-methyl]-8-methylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-benzonitrile; cis-4-[1-[(1-Hydroxy-cyclobutyl)-methyl]-8-methylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-3-methoxy-benzonitrile; cis-4-[8-Ethylamino-1-[(1-hydroxy-cyclobutyl)-methyl]-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-3-methoxy-benzonitrile; cis-2-[8-Ethylamino-1-[(1-hydroxy-cyclobutyl)-methyl]-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-benzonitrile; cis-5-[1-[(1-Hydroxy-cyclobutyl)-methyl]-8-methylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-4-methoxy-pyrimidine-2-carbonitrile; cis-2-[8-Dimethylamino-1-(oxetan-3-yl-methyl)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-benzamide; cis-4-Methoxy-5-(8-methylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)-pyrimidine-2-carbonitrile; cis-2-(8-Methylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)-benzamide; cis-8-Dimethylamino-3-[2-(3-oxo-piperazin-1-yl)-pyrimidin-5-yl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one; cis-3-(2-Cyclopropyl-pyrimidin-5-yl)-8-dimethylamino-8-phenyl-1,3-diazaspiro[4.5]decan-2-one cis-8-Dimethylamino-3-[4-methyl-6-(trifluoromethyl)-pyridin-3-yl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one; cis-8-Dimethylamino-3-(2-methylsulfonyl-phenyl)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one; cis-8-Dimethylamino-8-phenyl-3-(2-piperazin-1-yl-pyrimidin-5-yl)-1,3-diazaspiro[4.5]decan-2-one; trans-2-(8-Ethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)-benzamide; cis-2-(8-Ethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)-benzamide; cis-2-(8-Ethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)-benzonitrile; cis-2-(8-Ethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)-benzonitrile; cis-3-[5-(8-Dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)-pyrimidin-2-yl]-benzonitrile; cis-8-Dimethylamino-3-[2-(4-methylsulfonyl-piperazin-1-yl)-pyrimidin-5-yl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one; cis-3-[5-(8-Dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)-pyrimidin-2-yl]-benzamide cis-8-[(Cyclopropyl-methyl)-methyl-amino]-8-phenyl-3-[2-(trifluoromethyl)-pyrimidin-5-yl]-1,3-diazaspiro[4.5]decan-2-one; cis-8-Dimethylamino-3-[2-(4-methyl-piperazine-1-carbonyl)-pyrimidin-5-yl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one; trans-4-(8-Ethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)-3-methoxy-benzonitrile; cis-4-(8-Ethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)-3-methoxy-benzonitrile; cis-3-[2-(4-Acetyl-piperazin-1-yl)-pyrimidin-5-yl]-8-dimethylamino-8-phenyl-1,3-diazaspiro[4.5]decan-2-one; cis-8-Dimethylamino-8-phenyl-3-(2-pyridin-4-yl-pyrimidin-5-yl)-1,3-diazaspiro[4.5]decan-2-one; cis-8-Dimethylamino-8-phenyl-3-(2-pyridin-3-yl-pyrimidin-5-yl)-1,3-diazaspiro[4.5]decan-2-one; cis-5-(8-Dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)-N-(2-hydroxy-ethyl)-pyrimidine-2-carboxylic acid amide; cis-5-(8-Dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)-pyrimidine-2-carboxylic acid amide; cis-8-Dimethylamino-3-[2-morpholin-4-yl-4-(trifluoromethyl)-pyrimidin-5-yl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one; cis-4-[5-(8-Dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)-pyrimidin-2-yl]-benzonitrile; cis-5-(8-Ethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)-4-methoxy-pyrimidine-2-carbonitrile; trans-5-(8-Ethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)-4-methoxy-pyrimidine-2-carbonitrile; cis-8-Dimethylamino-3-[2-(morpholine-4-carbonyl)-pyrimidin-5-yl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one; cis-2-[4-[5-(8-Dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)-pyrimidin-2-yl]-piperazin-1-yl]-acetic acid methyl ester; cis-8-Dimethylamino-3-[2-(methylsulfonyl-methyl)-phenyl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one; cis-8-Dimethylamino-3-(4-methyl-2-morpholin-4-yl-pyrimidin-5-yl)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one; cis-8-Dimethylamino-3-[2-(1,1-dioxo-[1,4]thiazinan-4-yl)-pyrimidin-5-yl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one; cis-8-Dimethylamino-3-(4-fluoro-pyridin-3-yl)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one; cis-5-(8-Dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)-N-(2-hydroxy-ethyl)-N-methyl-pyrimidine-2-carboxylic acid amide; cis-5-(8-Dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)-2-morpholin-4-yl-isonicotinonitrile; cis-4-(8-Dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)-benzamide; cis-8-Dimethylamino-3-(2-fluoro-4-methylsulfonyl-phenyl)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one; cis-4-(8-Dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)-3-fluoro-benzonitrile; cis-4-(8-Dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)-3,5-difluoro-benzonitrile; cis-8-Dimethylamino-3-(2-methoxy-pyrimidin-5-yl)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one; cis-3-[2-(Benzylamino)-pyrimidin-5-yl]-8-dimethylamino-8-phenyl-1,3-diazaspiro[4.5]decan-2-one; cis-8-Dimethylamino-3-[2-(4-fluorophenyl)-pyrimidin-5-yl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one; trans-8-Benzyl-8-dimethylamino-3-(2-morpholin-4-yl-pyrimidin-5-yl)-1,3-diazaspiro[4.5]decan-2-one; cis-8-Benzyl-8-dimethylamino-3-(2-morpholin-4-yl-pyrimidin-5-yl)-1,3-diazaspiro[4.5]decan-2-one; cis-8-Dimethylamino-8-phenyl-3-(2-pyridin-2-yl-pyrimidin-5-yl)-1,3-diazaspiro[4.5]decan-2-one; cis-4-(8-Dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)-3,5-difluoro-benzamide; cis-4-(8-Dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)-3-fluoro-benzamide; cis-8-Benzyl-8-dimethylamino-3-[2-(trifluoromethyl)-pyrimidin-5-yl]-1,3-diazaspiro[4.5]decan-2-one; trans-8-Benzyl-8-dimethylamino-3-[2-(trifluoromethyl)-pyrimidin-5-yl]-1,3-diazaspiro[4.5]decan-2-one; cis-8-Dimethylamino-8-thiophen-2-yl-3-[2-(trifluoromethyl)-pyrimidin-5-yl]-1,3-diazaspiro[4.5]decan-2-one; trans-8-Dimethylamino-8-thiophen-2-yl-3-[2-(trifluoromethyl)-pyrimidin-5-yl]-1,3-diazaspiro[4.5]decan-2-one; cis-2-[2-(8-Dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)-phenoxy]-acetic acid; cis-8-Dimethylamino-8-phenyl-3-(2-piperidin-1-yl-pyrimidin-5-yl)-1,3-diazaspiro[4.5]decan-2-one; cis-8-Dimethylamino-8-phenyl-3-(2-pyrrolidin-1-yl-pyrimidin-5-yl)-1,3-diazaspiro[4.5]decan-2-one; cis-8-Dimethylamino-8-phenyl-3-(2-pyrimidin-5-yl-pyrimidin-5-yl)-1,3-diazaspiro[4.5]decan-2-one; cis-8-Dimethylamino-8-phenyl-3-[2-(piperazine-1-carbonyl)-pyrimidin-5-yl]-1,3-diazaspiro[4.5]decan-2-one; trans-8-Benzyl-8-dimethylamino-3-[4-methyl-6-(trifluoromethyl)-pyridin-3-yl]-1,3-diazaspiro[4.5]decan-2-one; cis-5-(8-Dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)-2-morpholin-4-yl-pyridine-4-carboxylic acid amide; cis-8-Dimethylamino-3-[2-(3,5-dimethyl-isoxazol-4-yl)-pyrimidin-5-yl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one; cis-3-[2-(Benzothiazol-6-yl)-pyrimidin-5-yl]-8-dimethylamino-8-phenyl-1,3-diazaspiro[4.5]decan-2-one; cis-8-Dimethylamino-3-[2-fluoro-4-(trifluoromethyl)-phenyl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one; cis-8-Dimethylamino-3-(6-morpholin-4-yl-pyridin-3-yl)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one; cis-8-Dimethylamino-8-phenyl-3-(2-phenyl-thiazol-4-yl)-1,3-diazaspiro[4.5]decan-2-one; cis-8-Dimethylamino-8-phenyl-3-[2-(tetrahydro-pyran-4-ylamino)-pyrimidin-5-yl]-1,3-diazaspiro[4.5]decan-2-one; cis-8-Dimethylamino-3-[2-(4-hydroxy-piperidin-1-yl)-pyrimidin-5-yl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one; cis-8-Dimethylamino-8-phenyl-3-(4-phenyl-thiazol-2-yl)-1,3-diazaspiro[4.5]decan-2-one; cis-8-Dimethylamino-8-phenyl-3-[2-(1H-pyrrolo[2,3-b]pyridin-1-yl)-pyrimidin-5-yl]-1,3-diazaspiro[4.5]decan-2-one; cis-8-Dimethylamino-8-phenyl-3-[2-(3,4,5-trifluoro-phenyl)-pyrimidin-5-yl]-1,3-diazaspiro[4.5]decan-2-one; cis-8-Dimethylamino-3-o-tolyl-8-phenyl-1,3-diazaspiro[4.5]decan-2-one; cis-8-Dimethylamino-3-m-tolyl-8-phenyl-1,3-diazaspiro[4.5]decan-2-one; cis-8-Dimethylamino-8-phenyl-3-p-tolyl-1,3-diazaspiro[4.5]decan-2-one; cis-8-Dimethylamino-8-phenyl-3-[4-(trifluoromethyl)-phenyl]-1,3-diazaspiro[4.5]decan-2-one; cis-8-Dimethylamino-8-phenyl-3-[3-(trifluoromethyloxy)-phenyl]-1,3-diazaspiro[4.5]decan-2-one; cis-8-Dimethylamino-8-phenyl-3-[4-(trifluoromethyloxy)-phenyl]-1,3-diazaspiro[4.5]decan-2-one; cis-2-(8-Dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)-benzoic acid methyl ester; cis-3-(8-Dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)-benzoic acid methyl ester; cis-4-(8-Dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)-benzoic acid methyl ester; cis-3-(1,3-Benzodioxol-5-yl)-8-dimethylamino-8-phenyl-1,3-diazaspiro[4.5]decan-2-one; cis-8-Dimethylamino-8-phenyl-3-quinolin-5-yl-1,3-diazaspiro[4.5]decan-2-one; cis-3-(2,3-Dihydro-1H-indol-6-yl)-8-dimethylamino-8-phenyl-1,3-diazaspiro[4.5]decan-2-one; cis-5-(8-Dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)-4-methyl-pyridine-2-carboxylic acid methyl ester; cis-8-Dimethylamino-3-(6-methoxy-4-methyl-pyridin-3-yl)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one; cis-8-Dimethylamino-3-[2-methyl-5-(trifluoromethyl)-2H-pyrazol-3-yl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one; cis-8-Dimethylamino-3-(3-methoxy-pyridin-2-yl)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one; cis-8-Dimethylamino-8-phenyl-3-[5-(trifluoromethyl)-pyridin-2-yl]-1,3-diazaspiro[4.5]decan-2-one; cis-5-(8-Dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)-nicotinonitrile; cis-8-Dimethylamino-3-(3-methyl-pyridin-2-yl)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one; cis-8-Dimethylamino-3-(6-methoxy-pyridin-3-yl)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one; cis-8-Dimethylamino-8-phenyl-3-[3-(trifluoromethyl)phenyl]-1,3-diazaspiro[4.5]decan-2-one; cis-3-(1,3-Benzodioxol-4-yl)-8-dimethylamino-8-phenyl-1,3-diazaspiro[4.5]decan-2-one; cis-8-Dimethylamino-3-[2-(2-oxo-1,3-dihydro-indol-4-yl)-pyrimidin-5-yl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one; cis-8-Dimethylamino-3-[2-(3,5-dimethyl-1H-pyrazol-1-yl)-pyrimidin-5-yl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one; cis-8-Dimethylamino-3-[2-(3-hydroxy-piperidin-1-yl)-pyrimidin-5-yl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one; cis-8-Dimethylamino-3-[2-(3-hydroxy-piperidin-1-yl)-pyrimidin-5-yl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one; cis-8-Dimethylamino-3-[2-[4-(2-hydroxy-ethyl)-piperazin-1-yl]-pyrimidin-5-yl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one; cis-2-[4-[5-(8-Dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)-pyrimidin-2-yl]-piperazin-1-yl]-acetic acid; cis-8-Dimethylamino-3-[2-(1-methyl-1H-pyrrolo[2,3-b]pyridin-4-yl)-pyrimidin-5-yl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one; cis-8-Benzyl-8-dimethylamino-3-[4-methyl-6-(trifluoromethyl)-pyridin-3-yl]-1,3-diazaspiro[4.5]decan-2-one; trans-8-Dimethylamino-3-[4-methyl-6-(trifluoromethyl)-pyridin-3-yl]-8-thiophen-2-yl-1,3-diazaspiro[4.5]decan-2-one; cis-8-Dimethylamino-3-[4-methyl-6-(trifluoromethyl)-pyridin-3-yl]-8-thiophen-2-yl-1,3-diazaspiro[4.5]decan-2-one; cis-8-Dimethylamino-3-[2-(1,1-dioxo-[1,4]thiazinan-4-yl)-4-(trifluoromethyl)-pyrimidin-5-yl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one; cis-8-Dimethylamino-8-(1-methyl-1H-benzoimidazol-2-yl)-3-[2-(trifluoromethyl)-pyrimidin-5-yl]-1,3-diazaspiro[4.5]decan-2-one; cis-8-Dimethylamino-8-(1-methyl-1H-benzoimidazol-2-yl)-3-[4-methyl-6-(trifluoromethyl)-pyridin-3-yl]-1,3-diazaspiro[4.5]decan-2-one; cis-8-Dimethylamino-3-[2-(2-hydroxy-ethylamino)-pyrimidin-5-yl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one; cis-3-[2-(Benzyl-methyl-amino)-pyrimidin-5-yl]-8-dimethylamino-8-phenyl-1,3-diazaspiro[4.5]decan-2-one; cis-5-(8-Dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)-N-[2-[2-[2-(2-methoxy-ethoxy)-ethoxy]-ethoxy]-ethyl]-pyrimidine-2-carboxylic acid amide; cis-8-Dimethylamino-3-[2-(1H-indazol-1-yl)-pyrimidin-5-yl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one; cis-8-Dimethylamino-3-[2-[(2-hydroxy-ethyl)-methyl-amino]-pyrimidin-5-yl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one; cis-3-(8-Dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)-benzamide; cis-8-Dimethylamino-3-[3-fluoro-5-(trifluoromethyl)-pyridin-2-yl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one; cis-8-Dimethylamino-3-(5-methyl-pyrazin-2-yl)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one; cis-8-Dimethylamino-3-(5-fluoro-pyrimidin-4-yl)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one; cis-8-Dimethylamino-3-(5-fluoro-pyrimidin-2-yl)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one; cis-8-Dimethylamino-8-phenyl-3-pyrazin-2-yl-1,3-diazaspiro[4.5]decan-2-one; cis-3-([2,1,3]Benzoxadiazol-5-yl)-8-dimethylamino-8-phenyl-1,3-diazaspiro[4.5]decan-2-one; cis-2-[2-(8-Dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)-phenoxy]-acetamide; cis-8-Dimethylamino-8-phenyl-3-(5-pyridin-4-yl-thiophen-2-yl)-1,3-diazaspiro[4.5]decan-2-one; cis-2-[2-(8-Dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)-phenoxy]-acetic acid methyl ester; cis-8-Dimethylamino-3-(2-morpholin-4-yl-pyrimidin-4-yl)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one; cis-3-[2-(3,4-Difluoro-phenyl)-pyrimidin-5-yl]-8-dimethylamino-8-phenyl-1,3-diazaspiro[4.5]decan-2-one; cis-2-[5-(8-Dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)-pyrimidin-2-yl]-benzonitrile; cis-3-(2-Amino-pyrimidin-5-yl)-8-dimethylamino-8-phenyl-1,3-diazaspiro[4.5]decan-2-one; cis-N-[5-(8-Dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)-pyrimidin-2-yl]-cyclopropanecarboxylic acid amide; cis-2-[4-[5-(8-Dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)-pyrimidin-2-yl]-piperazin-1-yl]-acetamide; cis-8-Dimethylamino-8-phenyl-3-(6-piperazin-1-yl-pyridin-3-yl)-1,3-diazaspiro[4.5]decan-2-one; cis-8-Dimethylamino-3-[6-(4-methyl-piperazin-1-yl)-pyridin-3-yl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one; cis-8-Dimethylamino-3-[2-(1,1-dioxo-[1,4]thiazinan-4-yl)-4-methyl-pyrimidin-5-yl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one; cis-8-Dimethylamino-8-phenyl-3-[2-(trifluoromethyl)-pyrimidin-5-yl]-1,3-diazaspiro[4.5]decan-2-one; cis-2-[8-Dimethylamino-1-(3-methoxy-propyl)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-pyrimidine-5-carbonitrile; cis-8-Dimethylamino-3-[2-(4-methyl-piperazin-1-yl)-pyrimidin-5-yl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one; cis-8-Dimethylamino-1-[(1-hydroxy-cyclobutyl)-methyl]-8-phenyl-3-[2-(trifluoromethyl)-pyrimidin-5-yl]-1,3-diazaspiro[4.5]decan-2-one; cis-2-[1-(3-Methoxy-propyl)-8-methylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-pyrimidine-5-carbonitrile; cis-8-Dimethylamino-8-phenyl-3-[6-(trifluoromethyl)-pyridin-3-yl]-1,3-diazaspiro[4.5]decan-2-one; cis-5-(8-Dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)-pyridine-2-carbonitrile; cis-8-Dimethylamino-3-(2-morpholin-4-yl-pyrimidin-5-yl)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one; cis-8-Dimethylamino-3-(2-methyl-pyrimidin-5-yl)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one; cis-8-Dimethylamino-1-[(2-methoxyphenyl)-methyl]-3-(2-methyl-pyrimidin-5-yl)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one; cis-1-[(1-Hydroxy-cyclobutyl)-methyl]-8-methylamino-8-phenyl-3-[2-(trifluoromethyl)-pyrimidin-5-yl]-1,3-diazaspiro[4.5]decan-2-one; cis-8-Dimethylamino-1-[(1-hydroxy-cyclobutyl)-methyl]-3-(2-methyl-pyrimidin-5-yl)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one; cis-1-[(1-Hydroxy-cyclobutyl)-methyl]-8-methylamino-8-phenyl-3-pyrimidin-5-yl-1,3-diazaspiro[4.5]decan-2-one; cis-5-(8-Dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)-4-methyl-pyridine-2-carbonitrile; cis-8-Dimethylamino-3-(2-methyl-pyrimidin-5-yl)-8-phenyl-1-(pyridin-2-yl-methyl)-1,3-diazaspiro[4.5]decan-2-one; cis-8-Dimethylamino-8-phenyl-3-pyrimidin-5-yl-1,3-diazaspiro[4.5]decan-2-one; cis-8-Dimethylamino-1-[(1-hydroxy-cyclobutyl)-methyl]-8-phenyl-3-pyrimidin-5-yl-1,3-diazaspiro[4.5]decan-2-one; cis-8-Amino-1-[(1-hydroxy-cyclobutyl)-methyl]-8-phenyl-3-[2-(trifluoromethyl)-pyrimidin-5-yl]-1,3-diazaspiro[4.5]decan-2-one; cis-8-Dimethylamino-3-(3-fluorophenyl)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one; cis-8-Dimethylamino-3-(3-methylsulfonyl-phenyl)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one; cis-8-Dimethylamino-3-(4-methylsulfonyl-phenyl)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one; cis-8-Dimethylamino-8-phenyl-3-pyridazin-3-yl-1,3-diazaspiro[4.5]decan-2-one; cis-3-Methoxy-4-(8-methylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)-benzonitrile; cis-8-Dimethylamino-3-(2-fluorophenyl)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one; cis-8-Dimethylamino-8-phenyl-3-(2-phenyl-pyrimidin-5-yl)-1,3-diazaspiro[4.5]decan-2-one; cis-8-Methylamino-1-(oxetan-3-yl-methyl)-8-phenyl-3-[2-(trifluoromethyl)-pyrimidin-5-yl]-1,3-diazaspiro[4.5]decan-2-one; cis-1-(Cyclopropyl-methyl)-8-methylamino-8-phenyl-3-[2-(trifluoromethyl)-pyrimidin-5-yl]-1,3-diazaspiro[4.5]decan-2-one; cis-4-(8-Dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)-benzonitrile; cis-8-Dimethylamino-3-(4-fluorophenyl)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one; cis-2-(8-Dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)-benzonitrile; cis-8-Ethylamino-1-[(1-hydroxy-cyclobutyl)-methyl]-8-phenyl-3-[2-(trifluoromethyl)-pyrimidin-5-yl]-1,3-diazaspiro[4.5]decan-2-one; cis-1-[(1-Hydroxy-cyclobutyl)-methyl]-8-methylamino-3-(2-methyl-pyrimidin-5-yl)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one; cis-8-Dimethylamino-3-[2-(morpholin-4-yl-methyl)-pyrimidin-5-yl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one; cis-8-Dimethylamino-3-[2-(methyl-tetrahydro-pyran-4-yl-amino)-pyrimidin-5-yl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one; cis-5-[8-Dimethylamino-1-[(1-hydroxy-cyclobutyl)-methyl]-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-[2-[2-[2-(2-methoxy-ethoxy)-ethoxy]-ethoxy]-ethyl]-pyrimidine-2-carboxylic acid amide; cis-1-(Cyclopropyl-methyl)-3-(2-fluoro-4-methylsulfonyl-phenyl)-8-methylamino-8-phenyl-1,3-diazaspiro[4.5]decan-2-one; cis-2-[[5-(8-Dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)-pyrimidin-2-yl]-methyl-amino]-acetamide; cis-2-[[5-(8-Dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)-pyrimidin-2-yl]amino]-acetamide; cis-1-(Cyclopropyl-methyl)-8-methylamino-3-[4-methyl-6-(trifluoromethyl)-pyridin-3-yl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one; cis-1-(Cyclopropyl-methyl)-8-dimethylamino-3-[4-methyl-6-(trifluoromethyl)-pyridin-3-yl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one; cis-N-[5-(8-Dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)-pyrimidin-2-yl]-thiophene-2-carboxylic acid amide; cis-N-[5-(8-Dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)-pyrimidin-2-yl]-benzamide; cis-8-Dimethylamino-8-phenyl-3-(5-phenyl-thiophen-2-yl)-1,3-diazaspiro[4.5]decan-2-one; cis-1-(Cyclopropyl-methyl)-8-dimethylamino-3-[2-(methylsulfonyl-methyl)-phenyl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one; cis-1-(Cyclopropyl-methyl)-8-methylamino-3-[2-(methylsulfonyl-methyl)-phenyl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one; cis-8-Dimethylamino-8-(3-fluorophenyl)-3-[2-(methylsulfonyl-methyl)-phenyl]-1,3-diazaspiro[4.5]decan-2-one; cis-8-Dimethylamino-8-(4-fluorophenyl)-3-[2-(methylsulfonyl-methyl)-phenyl]-1,3-diazaspiro[4.5]decan-2-one; cis-8-[Methyl-(tetrahydro-furan-3-yl-methyl)-amino]-8-phenyl-3-[2-(trifluoromethyl)-pyrimidin-5-yl]-1,3-diazaspiro[4.5]decan-2-one (enantiomer 1); cis-8-[Methyl-(tetrahydro-furan-3-yl-methyl)-amino]-8-phenyl-3-[2-(trifluoromethyl)-pyrimidin-5-yl]-1,3-diazaspiro[4.5]decan-2-one (enantiomer 2); cis-8-Dimethylamino-8-(3-fluorophenyl)-3-(4-methyl-2-morpholin-4-yl-pyrimidin-5-yl)-1,3-diazaspiro[4.5]decan-2-one; cis-3-[6-(4-Acetyl-piperazin-1-yl)-4-methyl-pyridin-3-yl]-8-dimethylamino-8-phenyl-1,3-diazaspiro[4.5]decan-2-one; cis-3-[2-(4-Acetyl-piperazin-1-yl)-4-methyl-pyrimidin-5-yl]-8-dimethylamino-8-phenyl-1,3-diazaspiro[4.5]decan-2-one; cis-8-Dimethylamino-3-(4-methyl-6-pyridin-4-yl-pyridin-3-yl)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one; cis-3-[2-(4-Acetyl-piperazin-1-yl)-4-(trifluoromethyl)-pyrimidin-5-yl]-8-dimethylamino-8-phenyl-1,3-diazaspiro[4.5]decan-2-one; cis-8-Dimethylamino-3-[2-(3-oxo-piperazin-1-yl)-4-(trifluoromethyl)-pyrimidin-5-yl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one; cis-8-Dimethylamino-3-isoquinolin-4-yl-8-phenyl-1,3-diazaspiro[4.5]decan-2-one; cis-8-Dimethylamino-3-isoquinolin-5-yl-8-phenyl-1,3-diazaspiro[4.5]decan-2-one; cis-8-Dimethylamino-8-phenyl-3-(1H-pyrrolo[2,3-b]pyridin-4-yl)-1,3-diazaspiro[4.5]decan-2-one; cis-8-Dimethylamino-8-phenyl-3-(2-pyridin-4-yl-thiazol-4-yl)-1,3-diazaspiro[4.5]decan-2-one; cis-8-[Methyl-(tetrahydro-furan-3-yl-methyl)-amino]-3-(2-morpholin-4-yl-pyrimidin-5-yl)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one (enantiomer 1); cis-8-[Methyl-(tetrahydro-furan-3-yl-methyl)-amino]-3-(2-morpholin-4-yl-pyrimidin-5-yl)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one (enantiomer 2); cis-3-[2-(Azetidin-1-yl)-pyrimidin-5-yl]-8-dimethylamino-8-phenyl-1,3-diazaspiro[4.5]decan-2-one; cis-3-[2-(3,3-Difluoro-azetidin-1-yl)-pyrimidin-5-yl]-8-dimethylamino-8-phenyl-1,3-diazaspiro[4.5]decan-2-one; cis-8-Dimethylamino-3-[6-morpholin-4-yl-5-(trifluoromethyl)-pyridin-3-yl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one; cis-8-Methylamino-3-[6-morpholin-4-yl-5-(trifluoromethyl)-pyridin-3-yl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one; cis-8-Dimethylamino-8-phenyl-3-[5-(trifluoromethyloxy)-pyridin-2-yl]-1,3-diazaspiro[4.5]decan-2-one; cis-8-Dimethylamino-3-(5-methylsulfonyl-pyridin-2-yl)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one; cis-6-(8-Dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)-nicotinonitrile; cis-3-[2-(4-Cyclopropyl-1H-[1,2,3]triazol-1-yl)-pyrimidin-5-yl]-8-dimethylamino-8-phenyl-1,3-diazaspiro[4.5]decan-2-one; cis-8-Dimethylamino-3-[4-methyl-2-(3-oxo-piperazin-1-yl)-pyrimidin-5-yl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one; cis-5-(8-Dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)-pyridine-2-carboxylic acid amide; cis-3-[4-(Azetidin-1-yl)-2-methyl-pyrimidin-5-yl]-8-dimethylamino-8-phenyl-1,3-diazaspiro[4.5]decan-2-one; cis-2-(8-Dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)-benzamide; cis-8-Dimethylamino-3-[2-(methylsulfonyl-methyl)-phenyl]-8-thiophen-2-yl-1,3-diazaspiro[4.5]decan-2-one; cis-8-Dimethylamino-8-(3-fluorophenyl)-3-[2-methyl-5-(trifluoromethyl)-2H-pyrazol-3-yl]-1,3-diazaspiro[4.5]decan-2-one; cis-8-Dimethylamino-3-(4-methyl-2-morpholin-4-yl-pyrimidin-5-yl)-8-thiophen-2-yl-1,3-diazaspiro[4.5]decan-2-one; cis-8-Dimethylamino-3-(6-methylsulfonyl-pyridin-3-yl)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one; cis-8-Dimethylamino-8-phenyl-3-(1H-pyrrolo[2,3-b]pyridin-5-yl)-1,3-diazaspiro[4.5]decan-2-one; cis-N-[5-(8-Dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)-pyrimidin-2-yl]-acetamide; cis-3-[2-(4-Methyl-piperazin-1-yl)-pyrimidin-5-yl]-8-[methyl-(tetrahydro-furan-3-yl-methyl)-amino]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one (enantiomer 1); cis-3-[2-(4-Methyl-piperazin-1-yl)-pyrimidin-5-yl]-8-[methyl-(tetrahydro-furan-3-yl-methyl)-amino]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one (enantiomer 2); cis-8-Dimethylamino-3-(4,6-dimethyl-2-morpholin-4-yl-pyrimidin-5-yl)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one; cis-8-Dimethylamino-3-(2-morpholin-4-yl-pyrimidin-5-yl)-8-thiophen-2-yl-1,3-diazaspiro[4.5]decan-2-one; cis-6-(8-Dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)-pyridine-3-carboxylic acid amide; cis-8-Dimethylamino-3-[2-methyl-5-(trifluoromethyl)-2H-pyrazol-3-yl]-8-thiophen-2-yl-1,3-diazaspiro[4.5]decan-2-one; cis-8-Dimethylamino-3-[2-[(2-hydroxy-ethyl)-methyl-amino]-pyrimidin-5-yl]-8-thiophen-2-yl-1,3-diazaspiro[4.5]decan-2-one; cis-8-Dimethylamino-3-[2-(2-oxo-1,3-dihydro-indol-4-yl)-pyrimidin-5-yl]-8-thiophen-2-yl-1,3-diazaspiro[4.5]decan-2-one; cis-8-Dimethylamino-3-[4-methyl-6-(3-oxo-piperazin-1-yl)-pyridin-3-yl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one; cis-8-Dimethylamino-3-(4-methyl-6-pyridin-2-yl-pyridin-3-yl)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one; cis-8-Dimethylamino-3-(4-methylsulfonyl-pyridin-3-yl)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one; cis-3-(Benzothiazol-7-yl)-8-dimethylamino-8-phenyl-1,3-diazaspiro[4.5]decan-2-one; cis-8-Dimethylamino-8-(4-fluorophenyl)-3-(4-methyl-2-morpholin-4-yl-pyrimidin-5-yl)-1,3-diazaspiro[4.5]decan-2-one; cis-2-[8-Dimethylamino-3-[4-methyl-6-(trifluoromethyl)-pyridin-3-yl]-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-1-yl]-N,N-dimethyl-acetamide; cis-8-Dimethylamino-3-[2-(2-methyl-1-oxo-2,3-dihydro-isoindol-4-yl)-pyrimidin-5-yl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one; cis-2-[[5-(8-Dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)-2-methyl-pyrimidin-4-yl]amino]-acetamide; cis-2-[3-(8-Dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)-pyridin-4-yl]-acetamide; cis-8-Dimethylamino-3-[4-(methylsulfonyl-methyl)-pyridin-3-yl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one; cis-8-Dimethylamino-3-[6-(4-methyl-3-oxo-piperazin-1-yl)-pyridin-3-yl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one; cis-8-Dimethylamino-3-(2,4-dimethyl-pyrimidin-5-yl)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one; cis-8-Dimethylamino-3-[2-(1-oxo-2,3-dihydro-isoindol-4-yl)-pyrimidin-5-yl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one; 2,2,2-trifluoro-acetic acid; cis-8-Dimethylamino-3-[6-[(2-hydroxy-ethyl)-methyl-amino]-5-(trifluoromethyl)-pyridin-3-yl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one; cis-8-Dimethylamino-8-phenyl-3-[2-[4-(trifluoromethyl)-1H-[1,2,3]triazol-1-yl]-pyrimidin-5-yl]-1,3-diazaspiro[4.5]decan-2-one; cis-8-Dimethylamino-3-[2-(4-isopropyl-1H-[1,2,3]triazol-1-yl)-pyrimidin-5-yl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one; cis-8-Dimethylamino-3-[6-(1,1-dioxo-[1,4]thiazinan-4-yl)-pyridin-3-yl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one; cis-5-(8-Dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)-2-morpholin-4-yl-nicotinonitrile; cis-8-Dimethylamino-3-(1-methylsulfonyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one; cis-8-Dimethylamino-3-(1H-indol-4-yl)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one; cis-8-Dimethylamino-3-(2-hydroxy-benzooxazol-7-yl)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one; cis-8-Dimethylamino-3-[2-fluoro-4-(trifluoromethyloxy)-phenyl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one; cis-4-[5-(8-Dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)-pyrimidin-2-yl]-benzamide; 2,2,2-trifluoro-acetic acid; cis-8-Dimethylamino-3-(1-methyl-1H-pyrrolo[2,3-b]pyridin-4-yl)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one; cis-3-(1-Acetyl-1H-indol-4-yl)-8-dimethylamino-8-phenyl-1,3-diazaspiro[4.5]decan-2-one; cis-8-Dimethylamino-3-(1H-indol-3-yl)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one; cis-6-(8-Dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)-5-methyl-nicotinonitrile; cis-6-(8-Dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)-5-fluoro-nicotinonitrile; cis-8-Dimethylamino-3-[4-methyl-6-(trifluoromethyl)-pyridin-3-yl]-1-(2-oxo-2-pyrrolidin-1-yl-ethyl)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one; cis-6-(8-Dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)-5-methyl-pyridine-3-carboxylic acid amide; cis-6-(8-Dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)-5-fluoro-pyridine-3-carboxylic acid amide; cis-8-Dimethylamino-3-[4-methyl-6-(trifluoromethyl)-pyridin-3-yl]-8-m-tolyl-1,3-diazaspiro[4.5]decan-2-one; cis-3-(8-Dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)-isonicotinonitrile; cis-8-Dimethylamino-3-[3-fluoro-5-(2-oxo-1,3-dihydro-indol-4-yl)-pyridin-2-yl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one; cis-8-Dimethylamino-3-[4-methyl-6-(trifluoromethyl)-pyridin-3-yl]-8-[3-(trifluoromethyloxy)-phenyl]-1,3-diazaspiro[4.5]decan-2-one; cis-8-Dimethylamino-3-[4-methyl-6-(trifluoromethyl)-pyridin-3-yl]-8-[3-(trifluoromethyl)phenyl]-1,3-diazaspiro[4.5]decan-2-one; cis-8-Dimethylamino-8-(3-methoxyphenyl)-3-[4-methyl-6-(trifluoromethyl)-pyridin-3-yl]-1,3-diazaspiro[4.5]decan-2-one; cis-8-(5-Chloro-thiophen-2-yl)-8-dimethylamino-3-[4-methyl-6-(trifluoromethyl)-pyridin-3-yl]-1,3-diazaspiro[4.5]decan-2-one; cis-8-Dimethylamino-8-(3-fluorophenyl)-3-[4-methyl-6-(trifluoromethyl)-pyridin-3-yl]-1,3-diazaspiro[4.5]decan-2-one; cis-8-Dimethylamino-3-(2-methylamino-pyrimidin-5-yl)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one; cis-8-(5-Chloro-thiophen-2-yl)-8-dimethylamino-3-(4-methyl-2-morpholin-4-yl-pyrimidin-5-yl)-1,3-diazaspiro[4.5]decan-2-one; cis-N-[5-(8-Dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)-pyrimidin-2-yl]-N-methyl-cyclopropanecarboxylic acid amide; cis-N-[5-(8-Dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)-pyrimidin-2-yl]-N,2,5-trimethyl-2H-pyrazole-3-carboxylic acid amide; cis-3-[4,6-Bis(trifluoromethyl)-pyridin-3-yl]-8-dimethylamino-8-phenyl-1,3-diazaspiro[4.5]decan-2-one; cis-8-Dimethylamino-3-[2-[(2-hydroxy-ethyl)-methyl-amino]-quinazolin-6-yl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one; cis-8-Dimethylamino-3-(2-morpholin-4-yl-quinazolin-6-yl)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one; cis-8-[Methyl-(oxetan-3-yl-methyl)-amino]-8-phenyl-3-[2-(trifluoromethyl)-pyrimidin-5-yl]-1,3-diazaspiro[4.5]decan-2-one; cis-3-(1-Acetyl-1H-indol-3-yl)-8-dimethylamino-8-phenyl-1,3-diazaspiro[4.5]decan-2-one; cis-8-Dimethylamino-8-phenyl-3-quinazolin-6-yl-1,3-diazaspiro[4.5]decan-2-one; cis-5-(8-Dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)-2-(2-oxo-1,3-dihydro-indol-4-yl)-isonicotinonitrile; cis-N-[5-(8-Dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)-pyrimidin-2-yl]-N-methyl-tetrahydro-pyran-4-carboxylic acid amide; cis-N-[5-(8-Dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)-pyrimidin-2-yl]-N,2,2-trimethyl-propionamide; cis-8-Dimethylamino-3-[2-(1-methyl-2-oxo-1,3-dihydro-indol-4-yl)-pyrimidin-5-yl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one; cis-8-Dimethylamino-3-(2-morpholin-4-yl-1H-benzoimidazol-5-yl)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one; cis-8-Dimethylamino-8-(3-fluoro-5-methyl-phenyl)-3-[4-methyl-6-(trifluoromethyl)-pyridin-3-yl]-1,3-diazaspiro[4.5]decan-2-one; cis-8-Dimethylamino-3-[6-(2-oxo-1,3-dihydro-indol-4-yl)-pyridin-3-yl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one; cis-8-Dimethylamino-8-(3-hydroxyphenyl)-3-[4-methyl-6-(trifluoromethyl)-pyridin-3-yl]-1,3-diazaspiro[4.5]decan-2-one; cis-3-[6-(Azetidin-1-yl)-5-(trifluoromethyl)-pyridin-3-yl]-8-dimethylamino-8-phenyl-1,3-diazaspiro[4.5]decan-2-one; cis-3-[1-(Cyclopropyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-isonicotinonitrile; cis-3-[3,5-Bis(trifluoromethyl)-pyridin-2-yl]-8-dimethylamino-8-phenyl-1,3-diazaspiro[4.5]decan-2-one cis-8-Dimethylamino-3-(5-fluoro-6-morpholin-4-yl-pyridin-3-yl)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one; cis-8-(3-Chlorophenyl)-8-dimethylamino-3-[4-methyl-6-(trifluoromethyl)-pyridin-3-yl]-1,3-diazaspiro[4.5]decan-2-one; cis-8-Dimethylamino-3-[5-(2-oxo-1,3-dihydro-indol-4-yl)-pyridin-2-yl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one; cis-8-Dimethylamino-8-phenyl-3-[5-(trifluoromethyl)-[1,3,4]thiadiazol-2-yl]-1,3-diazaspiro[4.5]decan-2-one; cis-8-Dimethylamino-3-(2-oxo-1,3-dihydro-indol-4-yl)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one; cis-8-Dimethylamino-3-[2-[(2-hydroxy-ethyl)-methyl-amino]-1H-benzoimidazol-5-yl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one; cis-8-Dimethylamino-3-(5-methyl-6-morpholin-4-yl-pyridin-3-yl)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one; cis-1-(Cyclopropyl-methyl)-8-dimethylamino-8-(3-fluorophenyl)-3-(5-methylsulfonyl-pyridin-2-yl)-1,3-diazaspiro[4.5]decan-2-one; cis-1-(Cyclopropyl-methyl)-8-(3-fluorophenyl)-8-methylamino-3-(5-methylsulfonyl-pyridin-2-yl)-1,3-diazaspiro[4.5]decan-2-one; cis-1-(Cyclobutyl-methyl)-8-(3-fluorophenyl)-8-methylamino-3-[2-(trifluoromethyl)-pyrimidin-5-yl]-1,3-diazaspiro[4.5]decan-2-one; cis-1-(Cyclopropyl-methyl)-8-dimethylamino-8-(3-fluorophenyl)-3-[2-(trifluoromethyl)-pyrimidin-5-yl]-1,3-diazaspiro[4.5]decan-2-one; cis-1-(Cyclopropyl-methyl)-8-(3-fluorophenyl)-8-methylamino-3-[2-(trifluoromethyl)-pyrimidin-5-yl]-1,3-diazaspiro[4.5]decan-2-one; cis-8-Dimethylamino-8-(3-fluorophenyl)-3-[2-(trifluoromethyl)-pyrimidin-5-yl]-1,3-diazaspiro[4.5]decan-2-one; cis-1-(Cyclopropyl-methyl)-8-dimethylamino-8-(3-fluorophenyl)-3-[2-methyl-5-(trifluoromethyl)-2H-pyrazol-3-yl]-1,3-diazaspiro[4.5]decan-2-one cis-1-(Cyclopropyl-methyl)-8-(3-fluorophenyl)-8-methylamino-3-[2-methyl-5-(trifluoromethyl)-2H-pyrazol-3-yl]-1,3-diazaspiro[4.5]decan-2-one; cis-8-Methylamino-3-(4-methyl-2-morpholin-4-yl-pyrimidin-5-yl)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one; cis-3-[5-(Azetidin-1-yl)-3-methyl-pyridin-2-yl]-8-dimethylamino-8-(3-fluorophenyl)-1,3-diazaspiro[4.5]decan-2-one; cis-8-Dimethylamino-8-(3-fluorophenyl)-3-(5-methylsulfonyl-pyridin-2-yl)-1,3-diazaspiro[4.5]decan-2-one; cis-3-(6-(azetidin-1-yl)-4-fluoropyridin-3-yl)-8-(dimethylamino)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one; cis-3-(6-(azetidin-1-yl)pyridin-3-yl)-8-(dimethylamino)-8-(3-fluorophenyl)-1,3-diazaspiro[4.5]decan-2-one; cis-3-(1-(cyclopropanecarbonyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl)-8-(dimethylamino)-8-(3-fluorophenyl)-1,3-diazaspiro[4.5]decan-2-one; cis-8-(dimethylamino)-8-(3-fluorophenyl)-3-(1-(2-hydroxyethyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl)-1,3-diazaspiro[4.5]decan-2-one; cis-3-(1-(cyclopropylmethyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl)-8-(dimethylamino)-8-(3-fluorophenyl)-1,3-diazaspiro[4.5]decan-2-one; cis-8-(dimethylamino)-8-(3-fluorophenyl)-3-(1-(methylsulfonyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl)-1,3-diazaspiro[4.5]decan-2-one; cis-1-(cyclopropylmethyl)-8-(dimethylamino)-8-(3-fluorophenyl)-3-(1-(methylsulfonyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl)-1,3-diazaspiro[4.5]decan-2-one; cis-2-(5-(8-(dimethylamino)-8-(3-fluorophenyl)-2-oxo-1,3-diazaspiro[4.5]decan-3-yl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)-N,N-dimethylacetamide; cis-2-(5-(1-(cyclopropylmethyl)-8-(dimethylamino)-8-(3-fluorophenyl)-2-oxo-1,3-diazaspiro[4.5]decan-3-yl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)-N,N-dimethylacetamide; cis-8-(dimethylamino)-3-(1-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one; cis-8-(dimethylamino)-3-(3-fluoro-1H-pyrrolo[2,3-b]pyridin-5-yl)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one; cis-8-(dimethylamino)-8-phenyl-3-(1H-pyrrolo[2,3-c]pyridin-4-yl)-1,3-diazaspiro[4.5]decan-2-one; cis-8-(dimethylamino)-8-phenyl-3-(2-(pyridazin-4-yl)pyrimidin-5-yl)-1,3-diazaspiro[4.5]decan-2-one; cis-8-(dimethylamino)-3-(2-(2-oxo-1,2-dihydropyridin-4-yl)pyrimidin-5-yl)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one; cis-8-(dimethylamino)-8-(3-fluorophenyl)-3-(1-methyl-3-(thiophen-2-yl)-1H-pyrazol-5-yl)-1,3-diazaspiro[4.5]decan-2-one; cis-8-(dimethylamino)-8-(3-fluorophenyl)-3-(1-methyl-3-morpholino-1H-pyrazol-5-yl)-1,3-diazaspiro[4.5]decan-2-one; cis-8-(dimethylamino)-8-phenyl-1-(2,2,2-trifluoroethyl)-3-(2-(trifluoromethyl)pyrimidin-5-yl)-1,3-diazaspiro[4.5]decan-2-one; cis-8-(dimethylamino)-8-phenyl-3-(2-(trifluoromethyl)pyrimidin-5-yl)-1-(3,3,3-trifluoropropyl)-1,3-diazaspiro[4.5]decan-2-one; cis-3-(4-methyl-6-(trifluoromethyl)pyridin-3-yl)-8-(methylamino)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one; cis-3-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)-8-(methylamino)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one; cis-8-(dimethylamino)-8-(3-fluorophenyl)-3-(4-(methylsulfonyl)pyridin-3-yl)-1,3-diazaspiro[4.5]decan-2-one; cis-8-(dimethylamino)-3-(1-ethyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)-8-(3-fluorophenyl)-1,3-diazaspiro[4.5]decan-2-one; cis-3-(1-cyclopropyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)-8-(dimethylamino)-8-(3-fluorophenyl)-1,3-diazaspiro[4.5]decan-2-one; cis-8-(dimethylamino)-8-(3-fluorophenyl)-3-(1-(oxetan-3-ylmethyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl)-1,3-diazaspiro[4.5]decan-2-one; cis-8-(dimethylamino)-8-(3-fluorophenyl)-3-(1-(2-(methylsulfonyl)ethyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl)-1,3-diazaspiro[4.5]decan-2-one; cis-8-(dimethylamino)-8-(3-fluorophenyl)-3-(4-methyl-2-(methylamino)pyrimidin-5-yl)-1,3-diazaspiro[4.5]decan-2-one; cis-3-(2-cyclopropoxy-4-methylpyrimidin-5-yl)-8-(dimethylamino)-8-(3-fluorophenyl)-1,3-diazaspiro[4.5]decan-2-one; cis-N-(5-(8-(dimethylamino)-8-(3-fluorophenyl)-2-oxo-1,3-diazaspiro[4.5]decan-3-yl)-4-methylpyrimidin-2-yl)-N-methylcyclopropanecarboxamide; cis-N-(5-(8-(dimethylamino)-8-(3-fluorophenyl)-2-oxo-1,3-diazaspiro[4.5]decan-3-yl)-4-methylpyrimidin-2-yl)-N-methylpivalamide; cis-3-(4-(azetidin-1-yl)-2-(trifluoromethyl)pyrimidin-5-yl)-8-(dimethylamino)-8-(3-fluorophenyl)-1,3-diazaspiro[4.5]decan-2-one; cis-8-(dimethylamino)-8-(3-fluorophenyl)-3-(4-(oxetan-3-ylmethoxy)-2-(trifluoromethyl)pyrimidin-5-yl)-1,3-diazaspiro[4.5]decan-2-one; cis-3-(2-cyclopropyl-4-(2,2,2-trifluoroethoxy)pyrimidin-5-yl)-8-(dimethylamino)-8-(3-fluorophenyl)-1,3-diazaspiro[4.5]decan-2-one; cis-3-(2-cyclopropyl-4-((2-hydroxyethyl)(methyl)amino)pyrimidin-5-yl)-8-(dimethylamino)-8-(3-fluorophenyl)-1,3-diazaspiro[4.5]decan-2-one and the physiologically acceptable salts thereof.
 27. The compound according to claim 1 adapted for use in the treatment of pain.
 28. A medicament comprising a compound according to claim
 1. 29. A method of treating pain, said method comprising administering to a patient in need thereof an effective amount therefor of at leas one compound according to claim
 1. 30. A method of treating a disorder selected from the group consisting of neurodegenerative disorders, neuroinflammatory disorders, neuropsychiatric disorders, and substance abuse/dependence, said method comprising administering to a patient in need thereof an effective amount therefor of at least one compound according to claim
 1. 